The seed and soil hypothesis has long explained organotropic metastasis through biochemical compatibility between tumor cells and distant tissues. However, accumulating evidence points to the role of mechanobiology in this process. This review proposes a framework in which cellular mechanical memory, the persistent adaptation to physical cues, functions as a mechanical compass that influences metastatic destination. We analyze how cancer cells, conditioned by the physical properties of the primary tumor (such as stiffness and viscosity), are epigenetically programmed to colonize distant organs with compatible mechanical signatures. We examine stiffness matching in bone metastasis, where cells conditioned by fibrotic tumors preferentially home to rigid skeletal niches, mediated by pathways including YAP/TAZ and RUNX2. We then address the paradox of soft tissue metastasis (brain, liver), proposing that a dual mechanical memory enables adaptation to compliant, viscoelastic environments. The role of dynamic forces, including fluid shear stress and cyclic strain, is examined in the context of lung colonization. By synthesizing these findings, we establish a comparative framework in which multidimensional mechanical memory, spanning static stiffness, viscoelasticity, and dynamic forces, contributes to organotropism as a complementary determinant alongside biochemical signaling. This framework generates testable predictions: that pharmacological disruption of specific mechanosensors or epigenetic erasure of stiffness memory should alter organ-specific metastatic patterns in preclinical models. Such a mechanobiological and biomechanical perspective may open therapeutic opportunities aimed at disrupting these physical memories to reduce metastatic dissemination.
Microcalcifications are among the most reliable mammographic signs of breast cancer, particularly of non-palpable and in situ disease, yet for decades they were regarded as inert by-products of cellular degeneration-a view that delayed inquiry into their biology. A growing body of in vitro, ex vivo, and tissue-based evidence now reframes breast microcalcification as a process that can be actively regulated and cell-driven, recapitulating physiological and pathological mineralization elsewhere in the body. In this review, we synthesize the mechanistic basis of this paradigm shift and argue that mineral formation is not a passive marker but a participant in tumor biology. Two mineral species-calcium oxalate and calcium hydroxyapatite-carry different biological meaning and are separable on routine histopathology by birefringence and histochemistry. Hydroxyapatite can promote proliferation, matrix remodeling, and invasion, yet it is also the mineral of most benign calcifications, so its significance lies in composition and cellular origin, not presence alone. We discuss the osteomimetic program through which mammary tumor cells acquire bone-like mineralizing capacity, including the roles of alkaline phosphatase activity, ion transport, and PI3K-Akt signaling, and we distinguish osteomimicry-a phenotype of the tumor cell-from the bone metastatic niche that such cells may exploit. We then consider how mineral composition and microstructure encode the surrounding microenvironment and connect to clinical observations: association with HER2-positive disease, behavior under neoadjuvant chemotherapy, prognostic associations, and an emerging link with bone metastasis. We close with an integrated framework and a research agenda positioning mineral biology at the interface of the tumor microenvironment and metastatic progression.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase with structural criteria shared among members of the insulin receptor subfamily. ALK plays crucial physiological roles such as in neural tissue development as well as in thinness and body weight regulation. In addition, ALK is a key driver of systemic inflammation that may lead to lethal sepsis. The oncogenic potential of ALK was first described in 1994 when 2 independent research groups discovered that ALK is aberrantly expressed in a rare aggressive subtype of T-cell lymphoma descriptively known as anaplastic large-cell lymphoma. Later, it was found that the aberrant expression of ALK extends to include other neoplasms such as non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumors, and others. In these neoplasms, ALK plays a central oncogenic role by upregulating the activity of a comprehensive network of upstream and downstream survival systems, which causes tumor cell survival and proliferation. The development of selective ALK inhibitors has led to paradigm shift in how ALK-expressing tumors, particularly non-small cell lung cancer, are treated. More recently, ALK has been implicated in disturbing the integrity of the immune system and sustaining immune evasion. In this review, we highlight 3 decades of ALK research, briefly discuss its physiological and pathological roles with a focus on cancer and immunity, and provide an update on the clinical utilization and mechanisms of resistance to ALK inhibitors.
Pancreatic ductal adenocarcinoma (PDAC) is shaped by a mechanically abnormal tumor microenvironment (TME) in which dysregulated mechanotransduction promotes malignant progression and therapeutic resistance. Two coupled but distinct pressure states dominate this landscape: solid stress and interstitial fluid pressure (IFP). Solid stress arises from constrained tumor growth, stromal contractility, and extracellular matrix remodeling. By contrast, IFP reflects hydrostatic pressure within the interstitial fluid compartment and is elevated by vascular leakage, impaired drainage, and low tissue hydraulic conductivity. Together, these abnormalities compress vessels, disrupt transport, and activate mechanotransduction programs that reinforce malignant adaptation. Here we integrate solid stress and IFP within a unified pressure-state framework for PDAC. We examine how these forces shape tumor progression, drug transport, and therapeutic response. We then evaluate spheroid, organoid, hydrogel, bioprinted, and microfluidic models according to what they truly control, directly measure, or merely infer. This distinction separates pressure-relevant systems from pressure-reconstructing models. We also discuss stromal normalization and the emerging role of artificial intelligence and machine learning (AI/ML) in model engineering and patient stratification. Current computational approaches can optimize mechanically defined models and infer pressure-related tumor states from multimodal data. However, they still rely largely on surrogates rather than direct measurements of solid stress or IFP. Our framework defines the biomechanical validation required to develop clinically predictive models of PDAC mechanobiology.
Osteosarcoma arises in a mechanically active skeletal environment, but how physical cues shape tumor behavior, immunity, and pain remains poorly defined. This review examines PIEZO1 and PIEZO2 as compartment-specific mechanotransducers and distinguishes direct osteosarcoma evidence from disease-relevant preclinical findings and broader evidence from bone, immune, neural, and pain systems. PIEZO1 is best established in osteoblast-lineage cells and osteocytes, where it regulates bone remodeling and mechanical adaptation; its causal role in human osteosarcoma remains unresolved. In osteosarcoma models, PIEZO1-associated responses to stiffness and strain are linked to invasion, adhesion remodeling, YAP/TAZ signaling, and phenotypic plasticity. PIEZO2 is less well supported as a tumor-cell regulator and is more convincingly positioned in sensory neurons that mediate mechanically evoked bone cancer pain. PIEZO1 may also influence myeloid, dendritic-cell, and T-cell behavior, although this immune axis remains unvalidated in osteosarcoma. These compartment-specific roles expose a mechanotherapeutic paradox: pathways required for skeletal adaptation and repair may also be used by malignant or stromal compartments. Resolving this problem will require spatially resolved human studies, orthotopic immunocompetent models, and cell-type-selective perturbation.
The multi-functional protein N-acetyltransferase 10 (NAT10), highly conserved from bacteria to human, is a versatile enzyme with an N-acetyltransferase domain, an RNA helicase domain, and a tRNA-binding domain, known for its ability to acetylate proteins and multiple RNA species. Specifically, NAT10 was reported to catalyze the N4-acetylcytidine (ac4C) modification on tRNA, rRNA, mRNA, and even viral RNA and to regulate translation efficiency, RNA stability, and eventually gene expression. NAT10 draws increasing attention for its emerging roles in rewiring metabolism, including amino acid, lipid, and glucose metabolism, and modulating immune responses to drive cancer progression, metastasis, and therapeutic resistance. In this review, we provide a conceptual framework of how the dysfunction of the highly conserved NAT10 leads to tumorigenesis, metastasis, and therapeutic resistance. We also summarize the major findings that reveal how NAT10 regulates cancer metabolism and immune responses. Lastly, we review the opportunities and challenges of targeting NAT10 to treat cancer and overcome drug resistance.
Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates—the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)—and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.
Lung cancer progression is governed not only by tumour-intrinsic genetic alterations but also by dynamic communication between tumour cells and the surrounding microenvironment. An important component of this communication is the tumour secretome, comprising soluble factors and extracellular vesicles (EVs), which contribute to the regulation of tumour growth, invasion, immune evasion, and therapeutic resistance. Through these mechanisms, secretome components and EVs promote phenotypic plasticity, microenvironmental remodelling, and adaptive responses to hypoxia, immune surveillance, and therapeutic stress. Importantly, secretome-derived factors and EVs are released into accessible biofluids, including blood, bronchoalveolar lavage fluid, and pleural effusions, highlighting their potential as minimally invasive biomarkers. In this review, we examine the lung tumour secretome, including both soluble secreted factors and EVs, with an emphasis on their contributions to tumour progression, metastasis, immune modulation, and resistance to targeted therapies, immunotherapy, and radiation. We discuss methodological advances and persistent technical challenges in EV isolation, characterisation, and molecular profiling that influence reproducibility and interpretation. We further evaluate emerging clinical applications, including liquid biopsy, treatment monitoring, and therapeutic targeting, and consider their integration within precision oncology frameworks. Finally, we highlight key barriers to clinical translation and outline priorities for future research, including methodological standardisation, prospective clinical validation, and the development of strategies to target tumour-derived secretory signalling selectively.
Platelets are increasingly recognized as important contributors to tumor progression and metastatic dissemination. Platelets facilitate cancer cell survival, their safe transit through the hostile bloodstream, arrest at distant organ sites, and ultimate outgrowth into metastatic lesions. Although multiple platelet-dependent mechanisms have been implicated in cancer progression—including epithelial-mesenchymal transition and the provision of tumor-supportive growth factors—recent studies increasingly highlight immune modulation as a central mechanism underlying platelet-mediated metastasis. Accordingly, this review summarizes current evidence on the molecular and cellular mechanisms by which platelets regulate cytotoxic T lymphocyte and natural killer (NK) cell-mediated anti-tumor immune responses. Special attention is given to platelet-associated immune checkpoint pathways, including the expression and intercellular transfer of Programmed Death-Ligand 1 (PD-L1), as well as to the release of immunomodulatory mediators such as transforming growth factor-β1 (TGF-β1), thromboxane A₂ (TXA₂), and adenosine generated by platelet ectoenzymes. Finally, the potential implications of platelet-immune interactions for cancer therapy are discussed, with a particular focus on their relevance for immunotherapeutic strategies and metastatic disease control.
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasingly prevalent and accounts for 22–70
Prostate cancer is the second-highest cause of cancer-related incidence and the fifth-highest cause of cancer mortality in males. Prostate cancer is a heterogeneous disease with a wide spectrum of clinical behaviour, ranging from indolent to highly aggressive. Molecular approaches, such as genomic testing, can augment existing clinical risk stratifications and tailor management to the individual. Genomic tests that sample biopsy or surgical tissue can provide a molecular risk assessment and identify actionable therapy targets. Liquid biopsy, while still emerging, may provide a non-invasive alternative to tissue tests and enable longitudinal monitoring of tumour status. We first discuss the molecular landscape of prostate cancer, before providing a detailed overview of the molecular approaches available for early detection and prognostication. Furthermore, methodological considerations and barriers towards clinical implementation for these tests are discussed, highlighting areas of future research.
Neuroblastoma (NB) is the most common extracranial solid tumour of childhood and remains a leading cause of paediatric cancer mortality, particularly in high-risk disease driven by MYCN amplification. Although MYCN is a central oncogenic driver, its role as a transcription factor has limited direct therapeutic targeting, shifting attention toward downstream metabolic and microenvironmental dependencies. Increasing evidence indicates that MYCN-driven metabolic rewiring extends beyond tumour-intrinsic processes to reshape the tumour microenvironment (TME), influencing immune composition and stromal dynamics. Recent advances in single-cell and spatial profiling technologies have revealed substantial heterogeneity within the NB TME, highlighting complex interactions between tumour cells, immune populations, and stromal components. Among these, cancer-associated fibroblasts (CAFs) have emerged as key regulators of extracellular matrix architecture, immune modulation, and metabolic crosstalk. However, CAF identity, functional diversity, and lineage relationships in NB remain incompletely defined, with significant overlap between tumour-intrinsic mesenchymal programs and stromal fibroblast signatures. In this review, we synthesise current understanding of MYCN-driven metabolic reprogramming and its impact on CAF heterogeneity and immune regulation. We integrate insights from adult cancers with emerging data in NB to critically evaluate CAF functional states, including inflammatory and myofibroblastic programs, and their roles in shaping tumour progression, immune exclusion, and therapeutic response. By framing NB as a MYCN-remodelled tumour ecosystem, this review identifies key knowledge gaps in stromal biology and highlights the need to resolve CAF heterogeneity and tumour–stroma interactions. These insights have broader implications for MYC-driven malignancies and support the development of integrated therapeutic strategies targeting both tumour cells and their supportive microenvironment.
The global incidence of rectal cancer (RC) is increasing at an alarming rate, with over 50
Sarcomas are rare in adults but constitute a substantial fraction of pediatric malignancies and are characterized by a high propensity for hematogenous dissemination and poor outcomes once metastatic. Yet, most mechanistic understanding of metastasis derives from carcinomas and is frequently extrapolated to sarcomas despite major biological differences. This review synthesizes current evidence on sarcoma metastasis and highlights key knowledge gaps across the metastatic cascade. It frames sarcomas as malignancies often arising from mesenchymal stromal cells, whose intrinsic motility, plasticity, and stem-like features may predispose transformed cells to dissemination without requiring a classic epithelial-to-mesenchymal transition program. The concept of metastasis-initiating cells is discussed in the context of sarcoma cancer stem cell biology, clonal evolution, and epigenetic reprogramming, emphasizing that the relative genomic simplicity of certain pediatric sarcomas driven by recurrent fusion oncogenes may provide powerful models to dissect metastasis dependencies. The review examines how the sarcoma tumor microenvironment, often immunosuppressive and macrophage-rich, may shape invasion, intravasation, survival in circulation, extravasation, and organotropism, particularly the strong predilection for pulmonary metastasis. It summarizes emerging data on circulating tumor cells and complementary liquid biopsy approaches, while underscoring technical limitations caused by sarcoma heterogeneity and lack of robust markers. Finally, the review appraises current treatment limitations for metastatic sarcoma and argues that improved mechanistic resolution, especially of plasticity, epigenetic states, microenvironmental interactions, and dormancy, will be essential to identify actionable vulnerabilities and improve outcomes for patients with disseminated disease.
Cancer cachexia significantly impacts the quality of life of cancer patients, predicting therapy response and survival. Cachexia prevalence and severity increases over the course of disease progression, affecting up to 80
Pathological vasculogenic mimicry (VM) is the process by which aggressive tumor stem cells form perfusable, matrix-rich, vessel-like networks, facilitating tumor perfusion and metastasis. Several well-characterized VM drivers include hypoxia, acidity, growth factors, and inflammatory molecules. Likewise, canonical and non-canonical transitions, such as epithelial-to-mesenchymal, epithelial-to-endothelial, endothelial-to-mesenchymal, and epithelial-mesenchymal plasticity contribute to VM formation. In addition, atypical mechanisms such as cell–cell fusion, polyploidization, gene silencing, and processes associated with viral infections have also been linked to VM induction. Clinically, VM has been associated with poor prognosis, metastasis, and resistance to antiangiogenic, chemo- and radiotherapeutic compounds, which may independently trigger or exacerbate VM. Therapeutic strategies to fight this highly adaptive process include combination regimens that simultaneously inhibit angiogenesis and VM, thereby preventing the emergence of alternative survival mechanisms. Likewise, key nodes and signaling pathways involved in VM, such as Notch, Wnt, and PI3K/AKT, are under active preclinical evaluation, together with pro-differentiating factors that attenuate stem-associated traits. However, despite its therapeutic relevance, the mechanistic basis of VM remains insufficiently integrated, leaving a gap in biomedical literature. To address this, the aim of this review was to provide comprehensive coverage of current evidence encompassing both well-established processes associated with VM and those not yet fully characterized. Our work integrates the analysis of signaling pathways, key molecular players, lineage plasticity, and microenvironmental factors that orchestrate VM. In addition, therapeutic challenges and opportunities are also discussed.
Human epidermal growth factor receptor 2 (HER2) is a crucial oncogenic factor, highly expressing in various cancers, with urothelial carcinoma (UC) showing one of the highest levels of HER2 overexpression. HER2 serves as an ideal therapeutic target in UC. Current HER2-targeted therapies primarily include tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates (ADCs). Among these, ADCs combined with immunotherapy have shown outstanding clinical potential, which have changed the treatment landscape in UC. However, the assessment of HER2 status in UC is still facing major challenges. There is no unified consensus on testing methods and the definition of HER2 positivity, accompanied by significant spatiotemporal expression heterogeneity. These challenges significantly making HER2 assessment difficult in UC, hindering the more precise clinical application of HER2-targeted therapies especially ADCs. In this review, we focus on analyzing the current challenges in standardizing HER2 detection and positivity definitions in UC, elaborating on the spatiotemporal heterogeneity of HER2 expression, and systematically summarizing new HER2 testing methods. It is aimed to provide theoretical insights and new perspectives for HER2 testing and assessment in UC. In order to adress the challenges in HER2 assessment in UC, future researches should concentrate on establishing a unified standard for UC-specific HER2 assessment algorithm, and exploring new HER2 testing methods tailored to clinical needs.
Cancer genomics, molecular pathology, targeted therapy, and immunotherapy have transformed how tumors are diagnosed and treated, yet several problems remain hard to resolve prospectively, including the interpretation of variants of uncertain significance, variable penetrance, recurrent drug resistance, and the early trajectories that predispose later therapeutic failure. Many of these are fundamentally evolutionary questions about which adaptive routes are accessible under selection and how reproducibly they arise. Here, we make the case that yeast experimental evolution can serve cancer biologists as a practical upstream discovery platform, because its control, scale, and temporal resolution expose recurrent adaptive routes, transient intermediates, compensatory mechanisms, and genotype-to-fitness relationships that mammalian systems resolve only slowly. We organize representative studies by evolutionary dynamic, set out design principles and an operational workflow, and mark where these models are strong, where they mislead, and where fission yeast adds complementary strengths. Together, these elements frame yeast evolution as a way to prioritize and sharpen downstream validation in cancer systems.
Spheroids, organoids, and further three-dimensional cellular models represent an intermediate stage of supra-cellular complexity between monolayered cell cultures and animal models. In the present review, we identified conditions in which spheroids and organoids could replace animal models in biomedical research, using long noncoding RNA (lncRNA) research in cancer as a study object. In tumor spheroids and patient-derived organoids, chemosensitivity can be enhanced through therapeutic overexpression or silencing of specific lncRNAs (depending on the lncRNA and context), which then decreases spheroid/organoid size or formation efficiency. These outcomes consistently mimic observations in xenograft mouse models, in which the same lncRNA intervention decreases tumor volume. Therefore, as a proxy of tumor growth assessment, animal models could be largely replaced with spheroids or organoids, taking advantage of their inexpensiveness and patient-specific features, respectively. The use of animal models could be restricted to bystander or pleiotropic effects, such as the assessment of parameters including metastasis and survival rates.
Tobacco use and especially smoking tobacco is a key risk factor in the development and the progression of head and neck squamous cell carcinoma (HNSCC). Continued smoking after diagnosis worsens treatment outcomes, survival rates, and quality of life significantly. This systematic review evaluates the effectiveness of smoking cessation interventions in HNSCC patients, aiming to provide an evidence-based foundation supporting smoking cessation efforts. A comprehensive search of five databases yielded 2492 studies, of which 11 met the inclusion criteria (total patient number = 1593). These covered a range of interventions, including behavioral counseling, pharmacotherapy (nicotine replacement therapy (NRT), bupropion, and varenicline), and digital or structural support tools. Reported cessation rates ranged from 23.9 to 74
