The Unfolded Protein Response (UPR) is an essential cellular process activated by the accumulation of unfolded proteins within the Endoplasmic Reticulum (ER), a condition referred to as ER stress. Three ER anchored receptors, IRE1, PERK and ATF6 act as ER stress sensors monitoring the health of the ER. Upon detection of ER stress, IRE1, PERK and ATF6 initiate downstream signaling pathways collectively referred to as the UPR. The overarching aim of the UPR is to restore ER homeostasis by reducing ER stress, however if that is not possible, the UPR transitions from a pro-survival to a pro-death response. While our understanding of the key signaling pathways central to the UPR is well defined, the same is not true of the subtle signaling events that help fine tune the UPR, supporting its ability to adapt to varying amplitudes or durations of ER stress. In this study, we demonstrate cross talk between the IRE1 and PERK branches of the UPR, wherein IRE1 via XBP1s signaling helps to sustain PERK expression during prolonged ER stress. Our findings suggest cross talk between UPR branches aids adaptiveness thereby helping to support the plasticity of UPR signaling responses.

Oxidative stress is caused by an imbalance in cellular redox state due to the accumulation of reactive oxygen species (ROS). While homeostatic levels of ROS are important for cell physiology and signaling, excess ROS can induce a variety of negative effects ranging from damage to biological macromolecules to cell death. Additionally, oxidative stress can disrupt the function of redox-sensitive organelles including the mitochondria and endoplasmic reticulum (ER). In the case of the ER, the accumulation of misfolded proteins can arise due to oxidative stress, leading to the onset of ER stress. To combat ER stress, cells initiate a highly conserved stress response called the unfolded protein response (UPR). While UPR signaling, within the context of resolving ER stress, is well characterised, how UPR mediators respond to and influence oxidative stress is less defined. In this review, we evaluate the interplay between oxidative stress, ER stress and UPR signaling networks. Specifically, we assess how UPR signaling mediators can influence antioxidant responses.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/or mark ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors.

Logue, Gorman, and Samali highlight a study by Guttman and colleagues (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202111068) that shows exogenous antigen peptides imported into the ER can activate the ER stress sensor IRE1α, attenuating cross-presentation by dendritic cells.

Logue, Gorman, and Samali highlight a study by Guttman and colleagues (2022. J. Cell Biol. https://doi.org/10.1083/jcb.202111068) that shows exogenous antigen peptides imported into the ER can activate the ER stress sensor IRE1α, attenuating cross-presentation by dendritic cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.

BACKGROUND:We investigated the predictive value of 11 serum biomarkers for renal and mortality end points in people with CKD. METHODS:Adults with CKD (n=139) were enrolled from outpatient clinics between February 2014 and November 2016. Biomarker quantification was performed using two multiplex arrays on a clinical-grade analyzer. Relationships between biomarkers and renal and mortality end points were investigated by random forests and Cox proportional hazards regression. RESULTS:The cohort was 56% male. The mean age was 63 years and median (IQR) CKD-EPI eGFR was 33 (24-51) ml/min per BSA. A total of 56 (40%) people developed a composite end point defined as ≥40% decline in eGFR, doubling of serum creatinine, RRT, or death over median (IQR) follow-up of 5.4 (4.7-5.7) years. Prediction of the composite end point was better with random forests trained on serum biomarkers compared with clinical variables (area under the curve of 0.81 versus 0.78). The predictive performance of biomarkers was further enhanced when considered alongside clinical variables (area under the curve of 0.83 versus 0.81 for biomarkers alone). Patients (n=27, 19%) with high soluble TNF receptor-1 (≥3 ng/ml) and neutrophil gelatinase-associated lipocalin (≥156 ng/ml), coupled with low complement 3a des-arginine (<2368 ng/ml), almost universally (96%) developed the composite renal and mortality end point. C-reactive protein (adjusted hazard ratio, 1.4; 95% CI, 1.1 to 1.8), neutrophil gelatinase-associated lipocalin (adjusted hazard ratio, 2.8; 95% CI, 1.3 to 6.1) and complement 3a desarginine (adjusted hazard ratio, 0.6; 95% CI, 0.4 to 0.96) independently predicted time to the composite end point. CONCLUSIONS:Outpatients with the triad of high soluble TNF receptor-1 and neutrophil gelatinase-associated lipocalin coupled with low complement 3a des-arginine had high adverse event rates over 5-year follow-up. Incorporation of serum biomarkers alongside clinical variables improved prediction of CKD progression and mortality. Our findings require confirmation in larger, more diverse patient cohorts.

Stress‐induced apoptosis is mediated primarily through the intrinsic pathway that involves caspase‐9. We previously reported that in caspase‐9‐deficient cells, a protein complex containing ATG5 and Fas‐associated death domain (FADD) facilitated caspase‐8 activation and cell death in response to endoplasmic reticulum (ER) stress. Here, we investigated whether this complex could be activated by other forms of cell stress. We show that diverse stress stimuli, including etoposide, brefeldin A and paclitaxel, as well as heat stress and gamma‐irradiation, caused formation of a complex containing ATG5‐ATG12, FADD and caspase‐8 leading to activation of downstream caspases in caspase‐9‐deficient cells. We termed this complex the ‘stressosome’. However, in these cells, only ER stress and heat shock led to stressosome‐dependent cell death. Using in silico molecular modelling, we propose the structure of the stressosome complex, with FADD acting as an adaptor protein, interacting with pro‐caspase‐8 through their respective death effector domains (DEDs) and interacting with ATG5‐ATG12 through its death domain (DD). This suggests that the complex could be regulated by cellular FADD‐like interleukin‐1β‐converting enzyme–inhibitory protein (cFLIP L ), which was confirmed experimentally. This study provides strong evidence for an alternative mechanism of caspase‐8 activation involving the stressosome complex.

Chemotherapy is a common treatment for patients with cancer. Tumour resistance to chemotherapy (chemoresistance) results in tumour regrowth and nonresponsiveness to further chemotherapeutic challenge.Cancer cells release protumorigenic factors, termed the TCS, to prevent chemotherapy-dependent cytotoxicity.Chemotherapy exposure can also change the types and abundance of components in the TCS, a phenomenon known as therapy-induced TCS.The TCS and therapy-induced TCS promote tumour recurrence by enabling cancer cell survival and the expansion of CSCs, and preventing antitumour immunity. Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity. Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity. Chemotherapy is a common and successful therapeutic strategy for many patients with cancer as a neoadjuvant or adjuvant treatment to surgery. However, a significant number of patients relapse months or years later with a tumour that is resistant to further chemotherapeutic challenge, a feature known as chemoresistance. Many relapsing tumours are also associated with distant metastasis, which is the leading cause of cancer-related deaths [1.Chaffer C.L. Weinberg R.A. A perspective on cancer cell metastasis.Science. 2011; 331: 1559-1564Crossref PubMed Scopus (2555) Google Scholar,2.Dillekas H. et al.Are 90% of deaths from cancer caused by metastases?.Cancer Med. 2019; 8: 5574-5576Crossref PubMed Scopus (3) Google Scholar]. Therefore, it is critical to identify the mechanisms of chemoresistance to develop targeted therapies and improve the rate of relapse-free survival. Chemoresistance occurs through two mechanisms: intrinsic and acquired resistance. Intrinsic or inherent resistance arises in tumour cells harbouring mutations in cellular processes that prime the cell for survival during chemotherapy treatment. Cancer cells undergoing chemotherapy can also develop or acquire resistance through additional genetic modification or rewiring of intracellular signalling pathways that are known to be crucial for drug resistance [3.Holohan C. et al.Cancer drug resistance: an evolving paradigm.Nat. Rev. Cancer. 2013; 13: 714-726Crossref PubMed Scopus (2212) Google Scholar]. Several key cellular processes are involved in the development of chemoresistance, including drug activation or inactivation, DNA damage repair, modifications to drug targets, enhanced drug efflux, inactivation of apoptosis machinery, and increased autophagy [3.Holohan C. et al.Cancer drug resistance: an evolving paradigm.Nat. Rev. Cancer. 2013; 13: 714-726Crossref PubMed Scopus (2212) Google Scholar,4.Cree I.A. Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance.BMC Cancer. 2017; 17: 1-8Crossref PubMed Scopus (55) Google Scholar]. Tumour heterogeneity also contributes to a resistant phenotype due to the presence of genetically diverse clones within a tumour. Each of these populations may respond differently to treatment, resulting in the emergence of drug resistant clones. CSCs are a small subpopulation of cancer cells found within the tumour that are another cellular source of chemoresistance. These cells have similar characteristics to nontransformed stem cells, such as the ability to self-renew, express the embryonic factors Oct4, Sox2, and Nanog, and are capable of differentiating into committed tumour cells. Due to their inherent quiescent state, CSCs can evade the actions of drugs that target rapidly proliferating cells, and can limit drug toxicity due to increased expression of aldehyde dehydrogenase (ALDH), drug efflux pumps, and prosurvival proteins [5.Dagogo-Jack I. Shaw A.T. Tumour heterogeneity and resistance to cancer therapies.Nat. Rev. Clin. Oncol. 2018; 15: 81-94Crossref PubMed Scopus (480) Google Scholar,6.Barbato L. et al.Cancer stem cells and targeted therapies.Cells. 2019; 8: 926Crossref Google Scholar]. Ultimately, these characteristics allow CSCs to repopulate the tumour, resulting in tumour relapse and chemoresistance. In addition to these mechanisms, the tumour establishes the TME to promote tumour progression and chemoresistance. Secreted factors from tumour cells, also known as the TCS, enable the recruitment of various cell types required to form the TME, such as mesenchymal stromal cells, immune cells, and vascular endothelial cells, among others (Box 1). The TCS is defined as the collection of soluble proteins and insoluble vesicles secreted by the cancer cell into the extracellular space [7.Paltridge J.L. et al.The secretome in cancer progression.Biochim. Biophys. Acta Proteins Proteomics. 2013; 1834: 2233-2241Crossref Scopus (54) Google Scholar]. The TCS is critical for cell–cell communication and is utilised to influence the function of cells in the TME and shape the premetastatic niche [8.Karagiannis G.S. et al.Cancer secretomics reveal pathophysiological pathways in cancer molecular oncology.Mol. Oncol. 2010; 4: 496-510Crossref PubMed Scopus (97) Google Scholar]. Emerging evidence is establishing the TCS as a major contributor to the development of chemoresistance. In this review, we discuss the recent literature describing how components of the TCS confer resistance to cancer cells to prevent chemotherapy-induced cell death. We also describe important emerging evidence showing that chemotherapy can rewire the TCS to confer tumour cell resistance and how this further impacts cells within the TME to promote tumour regrowth post therapy.Box 1Cellular Components of the Tumour MicroenvironmentShaping of the TME during early stages of tumorigenesis supports essential processes required for cancer progression. Bone marrow-endothelial progenitors and nearby vascular endothelial cells are recruited to the tumour and stimulated to sprout new blood vessels (angiogenesis) by tumour-secreted factors, such as VEGF and basic fibroblast growth factor (bFGF) [132.Weis S.M. Cheresh D.A. Tumor angiogenesis: molecular pathways and therapeutic targets.Nat. Med. 2011; 17: 1359-1370Crossref PubMed Scopus (1109) Google Scholar]. This process is not only critical for supplying the tumour with oxygen and essential nutrients for growth, but also provides an avenue for circulating immune cells and bone marrow-derived cells to reach the TME. Stromal cells, such as mesenchymal stromal cells (MSCs), are recruited from the bone marrow through various chemokines, such as TGF-β, C-X-C motif chemokine ligand 12 (CXCL12), and platelet-derived growth factor (PDGF) and have been demonstrated to promote CSC expansion, immune cell recruitment, and metastasis [133.Chaturvedi P. et al.Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.Proc. Natl. Acad. Sci. U. S. A. 2014; 111: E2120-E2129Crossref PubMed Scopus (108) Google Scholar, 134.Luo J. et al.Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling.Oncogene. 2014; 33: 2768-2778Crossref PubMed Scopus (63) Google Scholar, 135.Ren G. et al.CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα.Cell Stem Cell. 2012; 11: 812-824Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. Tumour-MSCs can also differentiate into CAFs, which aid in ECM deposition and remodelling, and support tumour growth, metastasis, and chemoresistance [136.Raz Y. et al.Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer.J. Exp. Med. 2018; 215: 3075-3093Crossref PubMed Scopus (57) Google Scholar, 137.Goetz J.G. et al.Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.Cell. 2011; 146: 148-163Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 138.Feig C. et al.Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 20212-20217Crossref PubMed Scopus (671) Google Scholar, 139.Lotti F. et al.Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.J. Exp. Med. 2013; 210: 2851Crossref PubMed Scopus (166) Google Scholar]. Immune cells, such as monocytes, TAMs, MDSCs, tumour-associated neutrophils (TANs), dendritic cells, natural killer (NK) cells, B cells, cluster of differentiation (CD) 4+ and CD8+ T cells, and Tregs all form the tumour immune microenvironment in various combinations, in both solid and haematological cancers. Tumour-associated immune cells promote tumour growth and metastasis and sculpt an immunosuppressive environment to enable tumour-immune evasion. For example, CTLs have been observed to be excluded from the tumour due to a surrounding ‘border’ of TAMs, hypothetically preventing CTL infiltration [140.Beatty G.L. et al.Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages.Gastroenterology. 2015; 149: 201-210Abstract Full Text Full Text PDF PubMed Google Scholar]. By contrast, other cancers can be infiltrated with CTLs, but these CTLs are ‘exhausted’ due to interactions with immunosuppressive programmed death ligand 1 (PDL1+) tumour cells and leukocytes within the tumour, resulting in defective immune mediated-cancer cell killing [141.Iwai Y. et al.Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 12293-12297Crossref PubMed Scopus (1671) Google Scholar]. Overall, these various cell types promote cell survival under chemotherapy and evade antitumour immunity by supporting an immunosuppressive TME. Shaping of the TME during early stages of tumorigenesis supports essential processes required for cancer progression. Bone marrow-endothelial progenitors and nearby vascular endothelial cells are recruited to the tumour and stimulated to sprout new blood vessels (angiogenesis) by tumour-secreted factors, such as VEGF and basic fibroblast growth factor (bFGF) [132.Weis S.M. Cheresh D.A. Tumor angiogenesis: molecular pathways and therapeutic targets.Nat. Med. 2011; 17: 1359-1370Crossref PubMed Scopus (1109) Google Scholar]. This process is not only critical for supplying the tumour with oxygen and essential nutrients for growth, but also provides an avenue for circulating immune cells and bone marrow-derived cells to reach the TME. Stromal cells, such as mesenchymal stromal cells (MSCs), are recruited from the bone marrow through various chemokines, such as TGF-β, C-X-C motif chemokine ligand 12 (CXCL12), and platelet-derived growth factor (PDGF) and have been demonstrated to promote CSC expansion, immune cell recruitment, and metastasis [133.Chaturvedi P. et al.Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.Proc. Natl. Acad. Sci. U. S. A. 2014; 111: E2120-E2129Crossref PubMed Scopus (108) Google Scholar, 134.Luo J. et al.Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling.Oncogene. 2014; 33: 2768-2778Crossref PubMed Scopus (63) Google Scholar, 135.Ren G. et al.CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFα.Cell Stem Cell. 2012; 11: 812-824Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. Tumour-MSCs can also differentiate into CAFs, which aid in ECM deposition and remodelling, and support tumour growth, metastasis, and chemoresistance [136.Raz Y. et al.Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer.J. Exp. Med. 2018; 215: 3075-3093Crossref PubMed Scopus (57) Google Scholar, 137.Goetz J.G. et al.Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.Cell. 2011; 146: 148-163Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 138.Feig C. et al.Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 20212-20217Crossref PubMed Scopus (671) Google Scholar, 139.Lotti F. et al.Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.J. Exp. Med. 2013; 210: 2851Crossref PubMed Scopus (166) Google Scholar]. Immune cells, such as monocytes, TAMs, MDSCs, tumour-associated neutrophils (TANs), dendritic cells, natural killer (NK) cells, B cells, cluster of differentiation (CD) 4+ and CD8+ T cells, and Tregs all form the tumour immune microenvironment in various combinations, in both solid and haematological cancers. Tumour-associated immune cells promote tumour growth and metastasis and sculpt an immunosuppressive environment to enable tumour-immune evasion. For example, CTLs have been observed to be excluded from the tumour due to a surrounding ‘border’ of TAMs, hypothetically preventing CTL infiltration [140.Beatty G.L. et al.Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages.Gastroenterology. 2015; 149: 201-210Abstract Full Text Full Text PDF PubMed Google Scholar]. By contrast, other cancers can be infiltrated with CTLs, but these CTLs are ‘exhausted’ due to interactions with immunosuppressive programmed death ligand 1 (PDL1+) tumour cells and leukocytes within the tumour, resulting in defective immune mediated-cancer cell killing [141.Iwai Y. et al.Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 12293-12297Crossref PubMed Scopus (1671) Google Scholar]. Overall, these various cell types promote cell survival under chemotherapy and evade antitumour immunity by supporting an immunosuppressive TME. The healthy secretome comprises cytokines, growth factors, hormones, coagulation factors, enzymes, glycoproteins, and extracellular vesicles (EVs). A finely tuned secretome is essential for maintaining physiological homeostasis and represents a large fraction of the proteins synthesised in highly secretory tissues; for example, 70% of the transcripts in the pancreas encode secretory proteins [9.Uhlén M. et al.Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Google Scholar]. For secretory proteins to reach the plasma membrane, an N-terminal signal sequence is generated during protein synthesis to target them to the classical secretory pathway [10.Blobel G. Dobberstein B. Transfer of proteins across membranes: I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma.J. Cell Biol. 1975; 67: 835-851Crossref PubMed Google Scholar,11.Farhan H. Rabouille C. Signalling to and from the secretory pathway.J. Cell Sci. 2011; 124: 171-180Crossref PubMed Scopus (79) Google Scholar]. For proteins without a signal sequence or for EVs, unconventional mechanisms are used through pore formation, ABC transporters, and the generation of membrane-bound organelles [12.Rabouille C. Pathways of unconventional protein secretion.Trends Cell Biol. 2017; 27: 230-240Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar]. Changes in the abundance of components of the secretome are observed in many diseases, including cancer [13.Mustafa S. et al.Comparison of the tumor cell secretome and patient sera for an accurate serum-based diagnosis of pancreatic ductal adenocarcinoma.Oncotarget. 2017; 8: 11963-11976Crossref PubMed Scopus (4) Google Scholar, 14.Ziegler Y.S. et al.Integration of breast cancer secretomes with clinical data elucidates potential serum markers for disease detection, diagnosis, and prognosis.PLoS One. 2016; 11e0158296Crossref PubMed Scopus (9) Google Scholar, 15.Creaney J. et al.A proteomic analysis of the malignant mesothelioma secretome using iTRAQ.Cancer Genomics Proteomics. 2017; 14: 103-117Crossref PubMed Scopus (0) Google Scholar]. For example, a recent study demonstrated altered expression of tumour secretome genes across 32 cancer types compared with adjacent-normal tissue or healthy tissue from the same donor organ [16.Robinson J.L. et al.A systematic investigation of the malignant functions and diagnostic potential of the cancer secretome.Cell Rep. 2019; 26: 2622-2635Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The most commonly changed genes encoding components of the TCS tend to be downregulated compared with adjacent normal or healthy tissue, and are implicated in tumour suppression and inhibition of cell–cell and/or cell–matrix interactions. Increased TCS genes are less commonly shared across cancer types, but those that are encode extracellular matrix (ECM) structural proteins and modifiers, signalling proteins, such as receptors, and promoters of vascularisation [16.Robinson J.L. et al.A systematic investigation of the malignant functions and diagnostic potential of the cancer secretome.Cell Rep. 2019; 26: 2622-2635Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Cancers that exhibited an overall reduction in the expression of tissue-specific secretory genes also had reduced unfolded protein response (UPR) activation, which is an adaptive mechanism used to reduce the protein processing burden in the endoplasmic reticulum (ER), the entry point of the secretory pathway [17.Almanza A. et al.Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications.FEBS J. 2019; 286: 241-278Crossref PubMed Scopus (138) Google Scholar]. For some cancer types, a general reduction in tissue-specific secretome transcripts may be a way to limit secretory stress to allow cancer cells to survive. For other cancer types, such as multiple myeloma, there may be a global reduction in secretory transcripts, but a disproportionate increase in a minority of transcripts, such as immunoglobulins, leading to UPR activation (reviewed in [18.Nikesitch N. et al.Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance.Clin. Transl. Immunol. 2018; 7e1007Crossref PubMed Scopus (12) Google Scholar]). Taken together, this not only highlights the need for cancer cells to have a functioning secretory pathway to ensure cell survival and growth, but also demonstrates the potential of targeting the secretory pathway as an anticancer therapy. The most abundant components of the TCS are cytokines, growth factors, enzymes, glycoproteins, and EVs. Since the 1990s, the contribution of the cytokine family in mediating tumour relapse has been extensively studied. Early studies demonstrated that expression of the interleukin (IL) family of cytokines, such as IL-6 and IL-8, strongly correlated with tumour recurrence and poor responsiveness to therapy in various cancers [19.Zhang G. Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma.Anticancer Res. 1999; 19: 1427-1432PubMed Google Scholar,20.Yuan A. et al.Interleukin-8 messenger ribonucleic acid expression correlates with tumor progression, tumor angiogenesis, patient survival, and timing of relapse in non-small-cell lung cancer.Am. J. Respir. Crit. Care Med. 2000; 162: 1957-1963Crossref PubMed Google Scholar]. Mechanistic studies in cancer cell lines have identified multifaceted roles for the TCS in cancer development, such as evasion of chemotherapy-induced cell death (Figure 1) and here we describe how components of the TCS promote chemoresistance. ILs are a large family of cytokines that comprise growth factors, chemokines, and inducers of differentiation, and are critical during inflammation in response to infection, tissue injury, and disease [21.Turner M.D. et al.Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease.Biochim. Biophys. Acta Mol. Cell Res. 2014; 1843: 2563-2582Crossref PubMed Scopus (0) Google Scholar]. In 1986, cancer was described as ‘a wound that does not heal’ due to similarities observed during inflammation in wound healing and cancer [22.Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.N. Engl. J. Med. 1986; 315: 1650-1659Crossref PubMed Google Scholar]. Since then, inflammatory mediators, such as ILs, have been extensively linked with many aspects of tumour development and chemoresistance. Various ILs have been shown to protect cancer cells against chemotherapy treatment by increasing the expression of antiapoptotic and drug efflux proteins, and enhancing prosurvival signalling pathways. For example, IL-1β has been shown to protect pancreatic cancer cells from etoposide due to a nitric oxide (NO)-mediated reduction in caspase cleavage, potentially due to caspase S-nitrosylation and prevention of caspase-mediated cell death [23.Müerköster S.S. et al.Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1β and NO lead to inactivation of caspases.Oncogene. 2006; 25: 3973-3981Crossref PubMed Scopus (0) Google Scholar]. IL-6 and IL-8 also protect ovarian cancer cells from chemotherapy through increased expression of the ABC transporter multidrug resistance protein 1 (MDR1) and drug-detoxifying enzyme glutathione S-transferase Pi (GSTpi), as well as antiapoptotic proteins Bcl-2, Bcl-XL, and XIAP [24.Wang Y. et al.Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells.Cancer Lett. 2010; 295: 110-123Crossref PubMed Scopus (0) Google Scholar,25.Du J. et al.IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1).Cancer Chemother. Pharmacol. 2018; 81: 1111-1119Crossref PubMed Scopus (4) Google Scholar]. The TGF family encompasses a large number of growth factors and cytokines comprising the TGFβ and bone morphogenic protein (BMP) families [26.Batlle E. Massagué J. Transforming growth factor-β signaling in immunity and cancer.Immunity. 2019; 50: 924-940Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar]. TGFβ and BMPs have diverse roles in cancer and their function in epithelial–mesenchymal transition (EMT) and metastasis is well established [27.Hao Y. et al.TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis.Int. J. Mol. Sci. 2019; 20: 2767Crossref PubMed Scopus (101) Google Scholar,28.Zhang L. et al.BMP signaling and its paradoxical effects in tumorigenesis and dissemination.Oncotarget. 2016; 7: 78206-78218Crossref PubMed Scopus (37) Google Scholar]. The TGFβ and BMP families have also been implicated in therapy resistance, but BMPs in particular have been demonstrated to either promote or limit tumour relapse depending on the cancer type [29.Xian S. et al.BMP-4 genetic variants and protein expression are associated with platinum-based chemotherapy response and prognosis in NSCLC.Biomed. Res. Int. 2014; 88: 1-8Crossref Scopus (6) Google Scholar,30.Laatio L. et al.BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells.Tumor Biol. 2011; 32: 985-995Crossref PubMed Scopus (0) Google Scholar]. BMP signalling has also been shown to protect nonsmall cell lung cancer (NSCLC) and squamous-type cancer cells [both prone to epidermal growth factor receptor (EGFR) mutation and anti-EGFR resistance] from anti-EGFR therapy. For example, BMP-7 protects oral squamous cancer cells from cetuximab through SMAD1, -5, and -8 signalling processes [31.Yin J. et al.Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas.Cancer Lett. 2018; 414: 181-189Crossref PubMed Scopus (0) Google Scholar], and BMP–BMP receptor signalling confers resistance to EGFR-mutated lung squamous cancer cells through the Akt/mTOR signalling kinase p70S6K [32.Wang Z. et al.Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 9990-9995Crossref PubMed Scopus (24) Google Scholar]. This highlights the potential of stratifying squamous cancers based on BMP levels to predict patients who would benefit from anti-EGFR therapy. Secreted enzymes not only degrade the ECM to enable the migration and invasion of tumour cells, but can also free trapped secreted factors within the ECM, further enhancing the actions of the secretome in protumorigenic processes. Matrix metalloproteinase proteins (MMPs) are key proteases involved in ECM degradation and aid in tumour cell migration and invasion, angiogenesis, and immune evasion [33.Gialeli C. et al.Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting.FEBS J. 2011; 278: 16-27Crossref PubMed Scopus (973) Google Scholar]. 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Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity.

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma, is associated with a low 5-year survival and harsh treatment side effects, underscoring an urgent need for therapy. The unfolded protein response (UPR) is activated in response to endoplasmic reticulum (ER) stress, where three ER stress receptors, IRE1, PERK and ATF6, aim to restore cellular homeostasis. The UPR is pro-tumourigenic in many cancers. In this study, we investigate basal UPR activity in RMS. Basal activation of IRE1 and PERK was observed in RMS cell lines, which was diminished upon addition of the IRE1 RNase inhibitor, MKC8866, or PERK inhibitor, AMGEN44. UPR inhibition caused a reduction in cell viability, cell proliferation and inhibition of long-term colony formation in both subtypes of RMS. Alveolar RMS (ARMS) subtype was highly sensitive to IRE1 inhibition, whereas embryonal RMS (ERMS) subtypes responded more markedly to PERK inhibition. Further investigation revealed a robust activation of senescence upon UPR inhibition. For the first time, the UPR is implicated in RMS biology and phenotype, and inhibition of UPR signalling reduces cell growth, suggesting that the UPR may be a promising target in RMS.

The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPs). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1β into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1α, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1α RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1β processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1α signaling in conditions of excessive inflammasome formation.

Receptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity, but little is known about its role outside the immune system. Recently, RIP2 has been linked to chemoresistance of triple negative breast cancer (TNBC), the most aggressive breast cancer subtype for which there is an urgent need for targeted therapies. In this study we show that high expression of RIP2 in breast tumors correlates with a worse prognosis and a higher risk of recurrence. We also demonstrate that RIP2 confers TNBC cell resistance against paclitaxel and ceramide-induced apoptosis. Overexpression of RIP2 lead to NF-κB activation, which contributed to higher expression of pro-survival proteins and cell survival. Conversely, RIP2 knockdown inhibited NF-κB signaling, reduced levels of anti-apoptotic proteins and sensitized cells to drug treatment. Together, these data show that RIP2 promotes survival of breast cancer cells through NF-κB activation and that targeting RIP2 may be therapeutically beneficial for treatment of TNBC.

Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.

Tumour cells endure both oncogenic and environmental stresses during cancer progression. Transformed cells must meet increased demands for protein and lipid production needed for rapid proliferation and must adapt to exist in an oxygen- and nutrient-deprived environment. To overcome such challenges, cancer cells exploit intrinsic adaptive mechanisms such as the unfolded protein response (UPR). The UPR is a pro-survival mechanism triggered by accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), a condition referred to as ER stress. IRE1, PERK and ATF6 are three ER anchored transmembrane receptors. Upon induction of ER stress, they signal in a coordinated fashion to re-establish ER homoeostasis, thus aiding cell survival. Over the past decade, evidence has emerged supporting a role for the UPR in the establishment and progression of several cancers, including breast cancer, prostate cancer and glioblastoma multiforme. This review discusses our current knowledge of the UPR during oncogenesis, tumour growth, metastasis and chemoresistance.

Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress-induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2α, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress.

The VEGF family of pro-angiogenic factors has represented a pillar for targeted cancer therapy for more than a decade. In comparison, the field of protein homeostasis (proteostasis) focusing on the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, has just recently emerged as an attractive anti-cancer approach. Recent findings suggest that both signaling pathways are incontestably interrelated to ensure cell survival. Herein, we summarize recent findings that demonstrate how these two fundamental aspects of cancer cell survival intersect and provide genetic and pharmacological evidence of the interplay between angiogenic factors such as VEGF-A or PlGF and the individual members of the UPR such as IRE1, PERK and ATF6. We further describe how this interaction does not only affect the cancer cells, but also the surrounding microenvironmental niche that is also involved in tumor progression. Furthermore, by summarizing the recent therapeutic implications of both anti-angiogenic and proteostatic approaches, we emphasize how these novel findings could be used synergistically to improve cancer therapy.

Cancer immune surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognized by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumor cells by expressing death ligand cytokines of the tumor necrosis factor ligand family. However, some tumor cells can escape immune elimination and progress. Acquisition of resistance to the death ligand-induced apoptotic pathway can be obtained through cleavage of effector cell expressed death ligands into a poorly active form, mutations or silencing of the death receptors, or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/dysfunctional death ligand signaling curbs its cytotoxicity. Moreover, DRs can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signaling does not only give a passive resistance against cell death but actively drives tumor cell motility, invasion, and contributes to consequent metastasis. This dual contribution of the death receptor signaling in both the early, elimination phase, and then in the late, escape phase of the tumor immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumor-eliminating immune effector function even in the absence of activation of the immune system against the tumor. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.