Death Receptor (DR) ligands, such as CD95L and TRAIL, are historically considered as key players of tumour immunosurveillance through their ability to induce cell death. Yet, depending on the cellular context, their corresponding DR, CD95 and TRAILR1/2, also initiate various non-cytotoxic pathways and cellular functions and display multiple pro-tumoural functions across various cancer types. To unleash the full potential of the therapeutic targeting of DR signalling, it is therefore essential to understand the molecular mechanisms that tip the scales between their anti- and pro-tumoural effects. DR signalling is physiologically tightly regulated, and hence widely dysregulated in cancer, at multiple steps. Herein, focusing on the DR CD95, TRAILR1/2 and TNFR1, we first summarise their main signalling regulatory steps and therapeutic strategies developed for their targeting in cancer. Then, we focus on the emerging and sometimes controversial roles of cellular compartmentalisation in the regulation of DR signalling in cancer.
Na⁺-K⁺-2Cl− cotransporter 1 (encoded by SLC12A2) is a solute carrier overexpressed in colorectal cancer (CRC), but its functional role remains unclear. Here, we identify NKCC1 as a marker of normal intestinal stem cells, supported by its crypt-base localization, single-cell transcriptomics, and patient-derived organoids, while analyses of public colorectal cancer single-cell datasets further link NKCC1 expression to cancer stem cell populations. Surprisingly, analysis of CRC patient datasets revealed that tumors with lower SLC12A2 expression were associated with poorer relapse-free survival. By stably knocking down NKCC1 in cell lines and organoids, we demonstrate enhanced expression of stemness markers, altered oxidative stress pathways, and increased radioresistance. In contrast, pharmacological inhibition with bumetanide activates AKT/mTORC1 signaling, elevates reactive oxygen species (ROS), and sensitizes cells to oxidative stress. Together, these results highlight NKCC1 as a dual regulator of stemness and redox homeostasis, supporting its role as a potential key player in colorectal carcinogenesis.
Glioma stem cells (GSCs) are key drivers of glioblastoma (GBM) tumorigenesis, invasion, therapy resistance, and recurrence and exhibit remarkable phenotypic plasticity. Stanniocalcin 1 (STC1) has been implicated in tumor progression and cancer stemness; however, its role and the molecular mechanisms through which it shapes GSC plasticity and malignant traits remain poorly understood. Here, transcriptomic RNA sequencing identified STC1 as a malignancy-associated gene enriched in GBM and mesenchymal (MES)-like GSCs. Comprehensive bioinformatic analyses further validated that STC1 was highly expressed in MES-like GBM/GSCs and closely associated with poor patient survival. Functional studies revealed that STC1 promoted multiple malignant properties of GSCs, including self-renewal, migration, invasion, tumorigenicity, and cellular plasticity. Conversely, STC1 silencing attenuated these effects. Mechanistically, STC1 activated the NOTCH1/STAT3 signaling cascade, leading to transcriptional upregulation of GFPT2, a key rate-limiting enzyme of the hexosamine biosynthetic pathway. This subsequently enhanced global O-GlcNAcylation, including modification of P65, thereby facilitating GSC plasticity and malignant progression. Genetic and pharmacological interventions targeting this signaling axis effectively mitigated the oncogenic effects driven by STC1. In conclusion, our study reveals that STC1 is a key regulator of GSC phenotypic plasticity and aggressiveness through the NOTCH1/STAT3/GFPT2/O-GlcNAcylation pathway. These results provide new mechanistic insights into GBM progression and suggest that targeting STC1-associated signaling networks may represent a potential therapeutic strategy for GBM.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options, and the development of chemoresistance remains a major challenge for effective treatment. Our findings reveal that the CD44 variant isoform CD44v5 plays a crucial role in TNBC cisplatin resistance. Analyses of clinical samples, bioinformatic data, and cellular experiments demonstrated that CD44v5 was highly expressed in TNBC and correlated with tumor-associated macrophage (TAM) infiltration and poor therapeutic response. Mechanistically, TAMs enhanced cisplatin resistance through CD44v5-dependent mechanisms by releasing interleukin-4 (IL-4). CD44v5 amplified the IL-4/IL-4Rα/STAT3 signaling pathway, which upregulated SLC7A11 expression and inhibited ferroptosis. In addition, CD44v5 stabilized SLC7A11 on the cell membrane by preventing its internalization, which reduced reactive oxygen species (ROS) accumulation and promoted TNBC ferroptosis resistance. Furthermore, in vivo studies demonstrated that CD44v5 knockdown significantly enhanced the antitumor efficacy of cisplatin through suppression of SLC7A11 expression and induction of ferroptosis, accompanied by decreased IL-4Rα expression and reduced TAM infiltration. These findings indicate that CD44v5 contributes to cisplatin resistance by both reinforcing IL-4/IL-4Rα/STAT3 signaling and maintaining SLC7A11 membrane stability, highlighting CD44v5 as a potential therapeutic target for overcoming chemoresistance in TNBC.
Prostate cancer is the second most common malignancy in men. For patients who present metastatic disease, androgen deprivation therapy is the standard of care. Despite significant initial responses to anti-androgenic therapy, almost all patients progress to an incurable metastatic castration-resistant prostate cancer, facing a significant therapeutic challenge. Docetaxel is a taxane that improves response rates in these patients, but its efficacy is limited due to the development of resistance, which can be mediated through anti-apoptotic adaptations. Dynamic BH3 profiling is a functional assay that can anticipate tumors’ anti-apoptotic adaptation to treatment and guide the use of specific inhibitors such as BH3 mimetics or PROTACs. In this study, we elucidate that BCL-xL is the major pro-survival protein in prostate cancer cell lines after docetaxel treatment, which can be reverted using BH3 mimetics or PROTAC strategies against this protein. We also describe for the first time that the downregulation of HRK and BAD sensitizer BH3-only proteins due to docetaxel treatment leads to BCL-xL mediated resistance in prostate cancer cells. Finally, we introduce a new functional technology that detects mitochondrial permeabilization, enabling successful testing of this therapeutic combination directly in patient‑derived prostate cancer cells.
Dysregulation of androgen receptor (AR) signaling is a key molecular driver of prostate cancer development and its transition to castration-resistant disease. Although emerging evidence indicates that AR may influence ferroptosis by modulating lipid peroxidation and antioxidant systems, the complete transcriptional network through which AR regulates ferroptosis remains incompletely defined. In this study, we identify the transcription factor ZNF217 as a direct downstream target of AR, which is aberrantly upregulated in prostate cancer and associated with poor clinical outcomes. ZNF217 enhances the transcriptional activity of its downstream effector PROM2, thereby suppressing ferroptosis and promoting cell survival. Functional assays demonstrate that ZNF217 silencing markedly amplifies ferroptotic features, whereas ZNF217 overexpression partially alleviates ferroptosis-induced cellular damage. Building on these findings, we established a drug screening system based on ZNF217 expression and identified the compound RSL3 from a panel of 13 ferroptosis inducers, which potently suppresses ZNF217 expression. Further investigations revealed that combined treatment with RSL3 and the AR antagonist enzalutamide produced a synergistic antitumor response in cellular and animal models, accompanied by marked attenuation of AR/ZNF217/PROM2 pathway activity and reduced tumor burden. Collectively, these findings identify AR/ZNF217/PROM2 signaling as a central determinant of ferroptotic vulnerability in prostate cancer and suggest that targeting this pathway may enhance sensitivity to AR inhibition, providing a molecular rationale for combination therapy in castration-resistant prostate cancer.
Chromosomal rearrangements are hallmarks of many cancers, yet the mechanisms governing breakpoint selection remain incompletely understood. Emerging evidence suggests that sublethal apoptotic signaling may contribute to structural genome remodeling. Oxidative stress and inflammatory stimuli trigger caspase activation and the release of caspase-activated DNase (CAD), which preferentially cleaves DNA at matrix association regions/scaffold attachment regions (MAR/SARs) that anchor chromatin loops to the nuclear scaffold. When apoptotic execution is incomplete and cells undergo recovery, a process termed anastasis, CAD-induced double-strand breaks (DSBs) can be repaired through error-prone end-joining pathways, including classical non-homologous end joining (cNHEJ) and microhomology-mediated end joining (MMEJ), producing rearrangements enriched at MAR/SAR-associated genomic regions. Drawing on mechanistic studies in leukemia and experimental evidence in nasopharyngeal carcinoma (NPC), this review outlines a framework linking apoptotic DNA fragmentation, nuclear architecture, and error-prone repair to recurrent structural variations, and discusses how shared inflammation- and virus-associated oxidative stress may promote analogous mechanisms of breakpoint formation in other malignancies. The convergence of findings across hematologic and epithelial malignancies strengthens the biological plausibility and potential generalizability of this model across inflammation- and stress-associated cancers. This perspective suggests that at least a subset of cancer-associated chromosomal rearrangements may arise not purely as stochastic by-products of genomic instability, but as structured outcomes of dysregulated cell-death programs acting on vulnerable chromatin domains. Beyond its mechanistic implications, this framework may inform biomarker discovery through apoptosis-associated breakpoint features and highlight potential therapeutic vulnerabilities in apoptosis-surviving cells, including dependence on polymerase theta-mediated repair or regulation of apoptotic execution.
Obesity is a rapidly escalating global health challenge and a major, modifiable driver of cancer risk and poor outcomes across at least 13 malignancies, including endometrial, colorectal, breast, pancreatic, hepatic, renal, ovarian, and esophageal adenocarcinoma. Beyond endocrine and metabolic effects, obesity establishes a tumor-permissive systemic state characterized by adipose hypoxia, chronic inflammation, insulin resistance, and adipokine imbalance. Here, we synthesize evidence that extracellular vesicles (EVs) serve as a central mechanistic conduit through which these obesity-associated stress programs are transmitted to tumor and stromal compartments, driving cancer initiation, progression, immune evasion, metastasis, and therapy resistance. Obesity amplifies EV biogenesis and reprograms EV cargo through hypoxia- and inflammation-responsive signaling and altered endosomal trafficking, enriching EVs with coordinated lipid, RNA, and protein modules that durably rewire recipient cells. Functionally, obesity-conditioned EVs reinforce oncogenic growth and survival signaling, promote epithelial plasticity and angiogenesis, remodel the tumor microenvironment toward immune suppression and extracellular matrix reorganization, and facilitate pre-metastatic niche formation. Clinically, EVs provide a stable, information-rich substrate for liquid biopsy development, with emerging EV signatures showing promise for early detection, risk stratification, and longitudinal disease monitoring in obesity-associated cancers. We conclude by outlining key mechanistic, technological, and translational priorities required to advance EV-based biomarkers and to therapeutically disrupt obesity-driven intercellular communication.
Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy driven by rapid metastasis and a profoundly immunosuppressive microenvironment. While the surface glycoprotein CD52 is a known immunoregulator, its precise role in solid tumors remains controversial, partly due to its broad expression across diverse cell populations and its compartment-specific functions within the tumor microenvironment. In this study, we utilized integrated single-cell RNA sequencing (scRNA-seq), functional assays, and compartment-specific clinical validation to elucidate the tumor-intrinsic functions of CD52 in PDAC. We identified a highly plastic, restricted subpopulation of CD52-high malignant epithelial cells that actively drives metastasis initiation by enhancing cellular invasive capacity. Concurrently, we demonstrated that tumor-derived CD52 orchestrated a multi-layered immunosuppressive network that attenuates CD8 + T cell cytotoxicity, facilitating early immune evasion. Furthermore, by systematically separating expression sources, our clinical validation established that tumor-derived CD52 is a prognostic indicator of poor patient survival. These findings characterize CD52 as a critical, tumor-intrinsic driver of PDAC progression, highlighting its value as a prognostic biomarker and a therapy target in combination with immune checkpoint blockade to overcome innate therapeutic resistance in PDAC.
Extracellular matrix (ECM) stiffening is a biophysical hallmark of solid tumors. Cutaneous melanoma is an aggressive malignancy characterized by high heterogeneity and phenotypic plasticity in which melanoma cells switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and therapy-resistant state. However, the impact of ECM stiffness on the diverse cellular phenotypes of melanoma remains poorly defined. Here, we show that melanoma cell subpopulations differ in their responses to mechanical signals. Compared to melanocytic/transitory cells, dedifferentiated cells exhibited heightened sensitivity to stiff collagen matrices, characterized by increased cell spreading, focal adhesion maturation, YAP nuclear translocation and contractility. ECM stiffening enhanced proliferation, migration and invasion in dedifferentiated cells, whereas highly proliferative and poorly migratory melanocytic/transitory cells were less affected by collagen stiffness. Importantly, a soft ECM sensitized dedifferentiated cells, but not melanocytic/transitory cells, to BRAF/MEK inhibition. Mechanistically, the mechanosensitivity of dedifferentiated cells relies on collagen receptors DDR1 and DDR2, which control cytoskeleton reorganization and YAP mechanosignaling. Genetic or pharmacological inhibition of DDR, actomyosin contractility, or YAP suppressed stiffness-induced proliferation and migration, reduced traction forces, and restored sensitivity to targeted therapy in dedifferentiated cells. Conversely, ectopic DDR1/DDR2 expression confers mechanosensitive properties to melanocytic cells. Our results thus reveal that phenotypic plasticity endows dedifferentiated melanoma cells with increased addiction to mechanical cues and implicate DDR1/2-YAP-dependent signaling in this aggressive behavior.
Colorectal cancer (CRC) ranks second in cancer-related mortality worldwide. Its clinical intractability and chemoresistance pose significant challenges, often driven by cancer stem cells (CSCs). Wnt/β-catenin signaling is a lynchpin of CSC self-renewal, but targetable upstream drivers remain elusive. Using bioinformatics, we identified the proteoglycan SPOCK1 (encoding the protein Testican-1) as a Wnt-associated marker. High SPOCK1 gene expression predicted poor patient prognosis and reduced progression-free survival following first-line chemotherapy. In vitro assays demonstrated that Testican-1 levels modulated Wnt/β-catenin activity. Testican-1 downregulation inhibited β-catenin nuclear translocation and TCF/LEF-mediated transcription, leading to concurrent suppression of CRC proliferation and spheroid-forming potential. Conversely, Testican-1 overexpression promoted β-catenin nuclear translocation and TCF/LEF-mediated transcription, which enhanced CRC malignant properties. This Testican-1-driven pro-tumorigenic effect was reversed by the β-catenin/TCF/LEF inhibitor iCRT3, demonstrating Testican-1's dependence on Wnt transcriptional activation. We validated this functional role in vivo using a Testican-1-overexpressing xenograft model and ex vivo using patient-derived organoids (PDOs), both confirming increased growth and β-catenin nuclear localization. Furthermore, data-independent acquisition (DIA) mass spectrometry of Testican-1-overexpressing tumors showed enrichment in Wnt/β-catenin and pro-tumorigenic pathways, including c-Myc and oxidative phosphorylation. Notably, Testican-1 expression was associated with remodeling of the tumor microenvironment, characterized by desmoplastic features. In summary, our findings establish a novel Testican-1/Wnt/β-catenin axis driving CRC tumorigenesis and progression, positioning it as a promising therapeutic target to overcome Wnt-mediated progression and resistance.
The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), critically influences pancreatic ductal adenocarcinoma (PDAC) progression. Neuroendocrine differentiation (NED) is associated with aggressive tumor behavior and therapy resistance in multiple malignancies, yet its regulation within the PDAC environment is poorly characterized. Through integrated analysis of clinical specimens and transcriptomic datasets, we identified significant enrichment of NED markers correlating with poor patient outcomes. Single-cell RNA sequencing further identified Glycoprotein prostaglandin D2 synthase (PTGDS) as a CAF-derived factor potentially driving NED. Functional studies demonstrated that PTGDS secreted by CAFs robustly induced NED while enhancing proliferation, invasion, migration, and gemcitabine resistance in pancreatic cancer cells. Mechanistically, we established that PTGDS activates MAPK signaling through its membrane receptor PAQR9, and the pharmacological inhibition of MAPK signaling or knockdown of PAQR9 effectively reversed PTGDS-induced malignant phenotypes. These findings reveal a novel CAFs/PTGDS-PAQR9-MAPK signaling axis that promotes NED and drives PDAC progression, offering new therapeutic opportunities to overcome stromal-mediated chemoresistance.
The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.
Disulfidptosis is an emerging form of regulated cell death (RCD) that is mechanistically distinct from, yet closely interconnected with, classical cell death modalities such as apoptosis, ferroptosis, and cuproptosis. It is typically triggered in cells with high expression of solute carrier family 7 member 11 (SLC7A11, also known as xCT) under glucose-deprived conditions. In this context, nicotinamide adenine dinucleotide phosphate (NADPH) becomes depleted, and consequently the level of reduced glutathione (GSH) declines, which in turn compromises the cellular capacity to efficiently resolve aberrantly accumulated intracellular disulfide bonds. As a result, disulfide stress progressively builds up and ultimately promotes abnormal crosslinking, aggregation, and functional disruption of cytoskeletal proteins, thereby driving catastrophic cytoskeletal collapse and cell death. Because SLC7A11 overexpression represents a key metabolic hallmark across multiple cancer types, disulfidptosis provides a novel conceptual framework for exploiting tumor-specific metabolic vulnerabilities. Moreover, accumulating evidence across diverse malignancies suggests that disulfidptosis contributes to tumor progression. Meanwhile, recent studies have increasingly highlighted evolving drug delivery strategies and metabolic synergistic approaches that integrate disulfidptosis with other RCD programs, and, importantly, its impact on the tumor immune microenvironment is gradually being elucidated. In this review, we systematically summarize the definition, molecular mechanisms, and biological functions of disulfidptosis, emphasize recent advances in its synergistic interplay with other cell death modalities, and discuss its implications for cancer immunotherapy. Finally, we outline emerging drug delivery strategies designed to induce disulfidptosis in tumor cells, aiming to facilitate further exploration and translational development of disulfidptosis-based anticancer therapies.
The NRF2 pathway has emerged as a central regulator of cellular redox homeostasis, coordinating the expression of a broad array of genes that protect cells from oxidative and electrophilic stress. In the context of cancer, NRF2 has been recognized as a key driver of chemoresistance, as its sustained activation enhances antioxidant defenses, detoxification pathways, and metabolic adaptation, thereby promoting tumor cell survival under therapeutic stress. Beyond its canonical role in redox regulation, NRF2 also orchestrates the expression of multiple genes involved in ferroptosis, a non-apoptotic, iron-dependent form of cell death that has recently gained attention as a promising strategy to overcome drug resistance. Mechanistically, NRF2 modulates ferroptosis through several interconnected pathways, including the regulation of glutathione biosynthesis, lipid metabolism, and iron homeostasis, yet its impact is highly context-dependent and can vary according to cell type and metabolic state. In this review, we provide an overview of the interplay between NRF2 and ferroptosis, tracing the historical development of this network and highlighting the pivotal roles of specific NRF2 targets in controlling ferroptotic susceptibility. Finally, we discuss how targeted modulation of NRF2 may influence ferroptosis, offering a potential avenue for the design of innovative therapies aimed at selectively eradicating resistant tumors.
Earlier age at menarche has long been known to be associated with an increased risk of ovarian cancer (OC). However, the underlying mechanisms are not completely understood. Here, we report a paternally inherited imprinted gene, MKRN3, that is associated with central precocious puberty (CPP) and that plays a tumor suppressive role in OC. We found that genomic MKRN3 mutations are significantly more common in OC patients. Genomic mutations in MKRN3 and low MKRN3 expression levels are correlated with poor patient survival. The restoration of MKRN3 in MKRN3-inactivated OC cells significantly suppresses tumor growth and proliferation in vitro and in vivo. Ovary-specific knockout of endogenous MKRN3 accelerates P53 inactivation-induced tumorigenesis in mice. Mechanistically, CSDE1 was identified as a major substrate for MKRN3 in OC via mass spectrometry-based proteomics screens. MKRN3 regulates OC cell proliferation through proteolytic ubiquitination of CSDE1. Our comprehensive data reveal that the CPP-associated gene MKRN3 is a tumor suppressor in human OC. We propose that germline mutations in the MKRN3 gene might partially explain the association between precocious puberty and the risk of OC.
Mesothelioma is a rare tumour of mesothelial origin that is often diagnosed at advanced stages. Despite recent approval of immunotherapy, the prognosis of mesothelioma remains dismal. Growing evidence links tumour metabolism to the molecular mechanisms driving mesothelioma’s aggressiveness, therapeutic resistance and poor outcomes. Mesothelioma-specific metabolic alterations may be derived from asbestos-induced chronic inflammation, the mesothelial origin, the pleural microenvironment and tumour-stroma interactions, as well as recurrent genomic alterations that distinguish mesothelioma from malignancies of the lung parenchyma. Elucidating these metabolic alterations is therefore crucial for identifying exploitable vulnerabilities and improving therapeutic strategies. Key metabolic pathways, including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis and amino acid and lipid metabolism, are tightly interconnected within a dynamic network that regulates cell survival and proliferation. Metabolism also shapes tumour microenvironment by regulating redox homoeostasis, signalling and nutrient exchange. Considering these pathways in isolation provides an incomplete picture, and instead, studying them as a whole, and building a coherent metabolic map is essential for revealing context-specific dependencies. In this review, we summarise current knowledge of mesothelioma metabolism, highlighting how recurrent genetic alterations including CDKN2A, MTAP, BAP1, NF2 and TP53 influence metabolic phenotypes. We discuss experimental and therapeutic efforts that target individual metabolic branches and evaluate how these insights can inform a unified strategy to exploit metabolic weaknesses and guide the rational development of combination therapies.
Abstract Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities – including dependencies on FASN, SCD, and HMGCR – clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.
