Despite advancements in diagnostics and treatment, lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Identifying novel molecular mechanisms that regulate th...Despite advancements in diagnostics and treatment, lung adenocarcinoma (LUAD) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Identifying novel molecular mechanisms that regulate the progression of LUAD is crucial for improving therapeutic outcomes. Our study reveals that CRTAC1, a natural tumor suppressor, can block the integrin pathway and inhibit the growth and metastasis of LUAD cells. Specifically, our study reveals that CRTAC1 is downregulated significantly in LUAD tissues and that its expression correlates positively with patient survival. Functionally, CRTAC1 inhibits the proliferation, migration, and invasion of LUAD cells both in vitro and in vivo by suppressing integrin/FAK signaling. These findings highlight CRTAC1 as a potential therapeutic target for LUAD, offering new avenues for treatment strategies aimed at reducing tumor progression.
Innovative three-dimensional (3D) systems have become a focus of research due to their ability to better mimic cell-cell and cell-extracellular matrix interactions. Current advances in 3D modelling have the potential to...Innovative three-dimensional (3D) systems have become a focus of research due to their ability to better mimic cell-cell and cell-extracellular matrix interactions. Current advances in 3D modelling have the potential to transform pre-clinical research by providing a more biologically relevant recapitulation of the in vivo cell environment. Among the published 3D platforms there is a lack of adipose tissue and cancer complex models. Primarily thought to function in triglyceride storage, protection and heat production, adipose tissue is now recognised as a complex and dynamic endocrine organ that secretes factors such as free fatty acids and adipokines, which have been shown to play a role in carcinogenesis. Obesity, a major cause of adipose tissue dysfunction, has also been strongly linked to the development of several types of cancer. 3D model technologies offer an innovative way to investigate adipose tissue-cancer crosstalk by mimicking in vivo conditions. This review aims to present a perspective on the adipose tissue-cancer dynamics and provide an overview of the current 3D models used to reliably reproduce the adipose tissue-cancer interaction in vitro.
Despite advancements in therapeutic strategies, metastatic prostate cancer (mPCa) remains challenging to treat, with limited clinical efficacy and poor prognosis. Anoikis resistance in tumor cells is crucial for their su...Despite advancements in therapeutic strategies, metastatic prostate cancer (mPCa) remains challenging to treat, with limited clinical efficacy and poor prognosis. Anoikis resistance in tumor cells is crucial for their survival in the vascular system and plays a key role in metastasis. Therefore, investigating the molecular mechanisms of metastasis and anoikis resistance is essential for identifying novel therapeutic targets and strategies. In this study, we found that YEATS domain-containing 2 (YEATS2) plays a critical role in promoting PCa metastasis by suppressing anoikis. We observed that YEATS2 expression was elevated in mPCa and associated with poor clinical outcomes. Knockdown of YEATS2 reduced the metastatic potential of PCa cells both in vivo and in vitro, whereas its overexpression inhibited anoikis and promoted metastasis by upregulating the expression of the DNA damage repair gene RAD50. Mechanistically, YEATS2 increases chromatin accessibility at the RAD50 promoter region by recognizing H3K27ac and subsequently recruits the transcription factor NR2C2. Mirin suppressed lymph node metastasis of PCa cells in vivo. Our study demonstrated a novel function of the YEATS2/NR2C2/RAD50 axis in regulating DNA damage responses and anoikis resistance in PCa metastasis, highlighting an important pathway that drives metastatic progression and offering potential new strategies for treating mPCa.
Ferroptosis, a distinct form of programmed cell death characterized by the iron-dependent aberrant buildup of lipid peroxides, has emerged as a promising approach in cancer therapy. The KEAP1-NRF2 axis serves as a critic...Ferroptosis, a distinct form of programmed cell death characterized by the iron-dependent aberrant buildup of lipid peroxides, has emerged as a promising approach in cancer therapy. The KEAP1-NRF2 axis serves as a critical regulator of ferroptosis, exerting its suppressive effects by preserving cellular redox homeostasis and orchestrating the transcriptional activation of downstream antioxidant genes. NRF2 hyperactivation is frequently observed across multiple cancer types and is associated with tumor progression and therapeutic resistance. Here, we identified the transcription factor TFAP2C as a novel regulator of the KEAP1-NRF2 signaling pathway in ovarian cancer (OC). TFAP2C knockdown inactivated KEAP1-NRF2 signaling, consequently reducing cell viability while inducing the accumulation of reactive oxygen species (ROS) and ferrous iron (Fe²⁺). Additionally, a decrease in the mitochondrial membrane potential (MMP) was observed upon TFAP2C knockdown. These alterations collectively triggered ferroptosis, thereby inhibiting the progression of OC to some extent. Moreover, NRF2 knockdown partially attenuated the pro-proliferative and ferroptosis-resistant phenotypes driven by TFAP2C overexpression in OC. ChIP and dual-luciferase reporter gene assays confirmed that TFAP2C transcriptionally repressed KEAP1 expression, thereby weakening the ubiquitination degradation of NRF2 by KEAP1. The upregulation of TFAP2C expression stabilized the NRF2 protein, activated the NRF2-dependent transcriptional program, and strengthened cellular antioxidant defenses, ultimately conferring resistance to ferroptosis. Mechanistically, TFAP2C bound to the promoter region of KEAP1 and recruited histone deacetylases 1/2 (HDAC1/2), resulting in the deacetylation of H3K27 and subsequent transcriptional repression of KEAP1. In summary, our mechanistic investigations revealed TFAP2C as a novel oncogenic driver in OC and a key regulator of ferroptosis via its epigenetic modulation of the KEAP1-NRF2 axis. These findings highlight TFAP2C as a potential therapeutic target for ferroptosis-inducing therapies in OC patients with high TFAP2C expression.
25-Hydroxyvitamin D (25(OH)D), a metabolite of vitamin D, has demonstrated anticancer properties; however, the role of alternative splicing in mediating these effects remains poorly understood. In this study, we reveal f...25-Hydroxyvitamin D (25(OH)D), a metabolite of vitamin D, has demonstrated anticancer properties; however, the role of alternative splicing in mediating these effects remains poorly understood. In this study, we reveal for the first time that 25(OH)D exerts antitumor effects by promoting exon 13 skipping of KDM6A (KDM6A Δexon13), which suppresses the proliferation and stemness of breast cancer cells and lacks H3K27 demethylase activity. Mechanistically, CUT&Tag and RNA-seq analyses demonstrated that KDM6A Δexon13 induces the accumulation of H3K27me3 at the promoter region of TRAP1, thereby inhibiting its transcription. Consequently, the downregulation of TRAP1 reduces Smad2/3 phosphorylation. Furthermore, KHDRBS3 was identified as the splicing factor of KDM6A Δexon13 and was regulated by 25(OH)D. Notably, 25(OH)D exhibited a synergistic effect with GSK-J4, a specific inhibitor of KDM6A, in suppressing breast cancer cell growth. Collectively, our findings uncover a novel anticancer mechanism of 25(OH)D, highlight the critical role of KDM6A Δexon13 in breast cancer progression, and provide further evidence supporting the correction of 25(OH)D deficiency in breast cancer patients.
Programmed cell death protein 1 (PD-1), an immune checkpoint primarily expressed on T cells, plays a critical role in mediating tumor immune evasion. However, the role of PD-1 in non-immune cells remains poorly understoo...Programmed cell death protein 1 (PD-1), an immune checkpoint primarily expressed on T cells, plays a critical role in mediating tumor immune evasion. However, the role of PD-1 in non-immune cells remains poorly understood. Here, we report tumor cell-intrinsic PD-1 expression in malignant ascites from ovarian cancer patients. Using murine ovarian cancer models, we demonstrate that PD-1 directly promotes ovarian cancer progression. Moreover, malignant ascites markedly upregulates PD-1 expression in ID8 ovarian cancer cells, acting as a pathological amplifier that exacerbates PD-1-mediated oncogenic signaling cascades, including enhanced proliferation and metastasis both in vitro and in vivo. Mechanistically, soluble PD-L1 (sPD-L1) in ascites interacts with tumor cell-intrinsic PD-1, activating the MAPK/ERK signaling pathway through enhanced phosphorylation of ERK1/2. In contrast, PD-1 inhibition, achieved by genetic knockout or antibody blockade, reverses these tumor-promoting effects. Furthermore, pharmacological inhibition of phosphorylated ERK1/2 counteracts the tumor progression mediated by the PD-1 and prolongs survival in murine ovarian cancer models. Our study uncovers a previously unrecognized tumor-intrinsic PD-1-ERK signaling axis in ovarian cancer, that accelerates tumorigenesis and provides new insights and perspectives for PD-1/PD-L1 immune checkpoint therapy in ovarian cancer.
Lapeyronnie E, Granet C, Tricard J
… +11 more, Gallet F, Yassine M, Daverat H, Rovini A, Chermat A, Jauberteau MO, Bertin F, Melloni B, Vincent F, Naves T, Lalloué F
Lung cancer is the leading cause of cancer deaths worldwide and remains one of the most difficult to cure. Tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), are often aberrantly activated by...Lung cancer is the leading cause of cancer deaths worldwide and remains one of the most difficult to cure. Tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), are often aberrantly activated by gene mutation and drive tumor growth. Monotherapy with tyrosine kinase inhibitors targeting EGFR has shown initial efficacy, but their benefits tend to decline over time. EGFR acts as a transcription factor promoting the expression of oncogenic drivers, which, in turn, cooperate with canonical EGFR mutations to induce therapeutic resistance. This study reports that sortilin, a crucial regulator of cytoplasmic EGFR, attenuates its transducing function. Genome-wide chromatin binding assays revealed that sortilin interacts with gene regulatory elements occupied by EGFR. These results suggest a model in which sortilin exhibits potential tumor suppressor-like activity by concurrently binding to regulatory elements of cMYC. Sortilin expression in lung adenocarcinoma may be predictive of the efficacy of anti-EGFR therapies.
Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows promise in triple-negative breast cancer (TNBC), yet durable responses are limited by immune escape. Here, we identified tumor-derived bromodomain-containing...Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows promise in triple-negative breast cancer (TNBC), yet durable responses are limited by immune escape. Here, we identified tumor-derived bromodomain-containing protein 4 (BRD4) as a critical mediator of tumor-associated macrophage (TAMs)-driven immune evasion in TNBC. Using syngeneic TNBC mouse models, we found that BRD4 promotes PD-L1 expression on TAMs by increasing GM-CSF production from tumor cells. Mechanistically, BRD4 binds to the GM-CSF promoter enriched with H4K8 lactylation (H4K8La) and H3K27 acetylation (H3K27Ac). BRD4 further sustains pyruvate and lactate pools via upregulation of PKM2, thereby amplifying H4K8La and H3K27Ac on the basis of modifications at the GM-CSF locus. Functionally, exogenous GM-CSF supplementation rescued impaired tumor growth and defective activation of TAMs caused by BRD4 inhibition, establishing a direct BRD4-GM-CSF-TAMs regulatory axis. Therapeutically, combined treatment with the BRD4 inhibitor JQ1 or the first bromodomain (BD1) selective inhibitor MS402 and an anti-GM-CSF antibody markedly suppressed TNBC progression and converted the tumor immune microenvironment from "cold" to "hot". In conclusion, our study reveals a previously unrecognized metabolic-epigenetic mechanism through which BRD4 drives GM-CSF-dependent TAMs activation and immune evasion in TNBC. Targeting BRD4 in combination with GM-CSF blockade represents a promising therapeutic strategy to overcome immune resistance in this aggressive breast cancer subtype.
Non-small cell lung cancer (NSCLC) with spinal metastasis represents a clinical challenge due to its aggressive nature, limited treatment options, and profound impact on patient quality of life. Here, we report the devel...Non-small cell lung cancer (NSCLC) with spinal metastasis represents a clinical challenge due to its aggressive nature, limited treatment options, and profound impact on patient quality of life. Here, we report the development of an innovative upconversion mesoporous silica nanoparticle (UCMS) platform co-loaded with celecoxib and rose bengal (UCMS@CXB/RB), engineered to synergistically combine photodynamic therapy (PDT) and cyclooxygenase-2 (COX-2) inhibition. Upon near-infrared (NIR) irradiation, UCMS@CXB/RB generated abundant reactive oxygen species, triggered immunogenic cell death, and significantly suppressed prostaglandin E2 signaling, leading to reduced angiogenesis and improved antitumor immunity. In vitro and in vivo studies confirmed that this nanoplatform effectively remodeled the tumor microenvironment, inhibited tumor growth, and alleviated cancer-induced spinal dysfunction. Single-cell multi-omics analysis further revealed dynamic crosstalk among immune cells, tumor cells, and endothelial populations, providing mechanistic insights into the multifaceted therapeutic effects of UCMS@CXB/RB. Our results underscore the clinical potential of integrating PDT with targeted COX-2 blockade to address the complex pathophysiology of NSCLC spinal metastasis. This study presents a promising minimally invasive therapeutic strategy with strong translational relevance for managing metastatic NSCLC and improving patient outcomes.
Cuproptosis is involved in the proliferation, metastasis, and drug resistance formation development of renal cell carcinoma (RCC) by regulating lipid metabolism and oxidative stress levels in the tumor microenvironment,...Cuproptosis is involved in the proliferation, metastasis, and drug resistance formation development of renal cell carcinoma (RCC) by regulating lipid metabolism and oxidative stress levels in the tumor microenvironment, with Ferredoxin 1 (FDX1) as a core regulator. Proline-rich 15 (PRR15) is a proline-rich protein, that we previously found to inhibit the malignant progression of triple-negative breast cancer through the regulation of the phosphatidylinositol 3-kinase (PI3K) pathway and epithelial-mesenchymal transition (EMT) pathway. However, the role of PRR15 in cuproptosis and its molecular mechanisms remain unknown. This study found confirmed that PRR15 promotes cuproptosis and mitochondrial damage in RCC cells and inhibits tumor proliferation and metastasis, as demonstrated in vivo and in vitro. When RCC develops, PRR15 silencing activates the nuclear factor kappa-B (NF-κB) signaling pathway, which inhibits FDX1 expression, ultimately blocking the cuproptosis process and increasing tumor invasiveness. Conversely, overexpression of PRR15 reverses this phenotype. This study reveals for the first time the regulatory mechanism of the PRR15/NF-κB/FDX1 axis in cuproptosis in RCC, providing a new strategy for the treatment of RCC patients.
Stimulator of interferon genes (STING) agonists have shown promise in cancer immunotherapy by enhancing type I interferon (IFN-I) signaling. However, the antiviral effects of IFN-I can suppress viral replication, limitin...Stimulator of interferon genes (STING) agonists have shown promise in cancer immunotherapy by enhancing type I interferon (IFN-I) signaling. However, the antiviral effects of IFN-I can suppress viral replication, limiting their combination with oncolytic viruses. This study demonstrates that combining a naturally isolated Senecavirus A (SVA) strain with the STING agonist MSA-2 supports synergistic IFN-I activation across multiple tumor models. The combination induces robust innate and adaptive antitumor immune responses without impairing SVA replication. Transcriptomics, immunoblotting and early IRF7 nuclear translocation in B16‑F10 cells are consistent with engagement of the RIG‑I/MDA5-TBK1-IRF7 axis. In vivo, co‑treatment enhanced IFN‑β induction, increased CD8⁺ T‑cell infiltration and reduced tumor burden relative to monotherapies, whereas efficacy was not observed in athymic nude mice, supporting T‑cell dependence. Together, these data provide preclinical evidence that a rational oncolytic virus and STING combination can amplify antitumor immunity without overtly compromising viral persistence.
Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Although the transcription factor ETV5 is recognized for its oncogenic roles in tumor progression, its ro...Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Although the transcription factor ETV5 is recognized for its oncogenic roles in tumor progression, its role in remodeling the immunosuppressive microenvironment remains largely unexplored. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Genetic silencing of ETV5 in murine tumor models suppressed PMN-MDSCs differentiation from myeloid progenitors, reduced their tumor infiltration, and attenuated immunosuppressive function, resulting in enhanced cytotoxic T cell activity and delayed tumor progression. Mechanistically, ETV5 directly binds to the JH1 domain of JAK2, inducing its dimerization and phosphorylation, which activates STAT3 to transcriptionally upregulate CCL2 and recruit PMN-MDSCs. Therapeutically, ETV5 ablation synergized with anti-PD-L1 therapy to enhance tumor control, mirroring clinical observations where high ETV5 expression predicted immunotherapy resistance. Our study uncovers a non-canonical, transcription-independent role of ETV5 in orchestrating the JAK2/STAT3/CCL2 axis to sustain PMN-MDSC-mediated immune evasion, proposing ETV5 as a druggable target to overcome ICI resistance in solid tumors.
Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with a five-year survival rate below 20%. Elevated basal levels of endoplasmic reticulum stress (ERS) have recently emerged as a t...Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with a five-year survival rate below 20%. Elevated basal levels of endoplasmic reticulum stress (ERS) have recently emerged as a therapeutic vulnerability in OCa. We have previously shown that the tris-benzamide ERX-41 can induce ERS and cancer cell death in OCa by targeting LIPA. In this study, using iterative structure-activity relationship-guided studies to enhance activity in OCa, we identified a more potent ERX-41-derived analog, ERX-208. Importantly, ERX-208 consistently and significantly reduced cell viability in 23 OCa cell lines spanning five major histological OCa subtypes, with IC₅₀ values ranging from 50-100 nM, compared to ∼500 nM for ERX-41. Notably, ERX-208 showed minimal cytotoxicity toward normal ovarian surface epithelial cells, indicating cancer cell selectivity. ERX-208 induced apoptosis and suppressed colony formation in vitro in OCa cells. Mechanistic studies using RNA sequencing, Western blotting, RT-qPCR, transmission electron microscopy, and immunohistochemistry validated robust activation of ERS pathways upon ERX-208 treatment. Through in silico molecular docking simulation and confirmatory detailed site-directed mutagenesis, we identified that ERX-208 binds to LIPA over a broader interaction surface than ERX-41. At the 10 mg/kg dose, ERX-208 demonstrated favorable biodistribution, no observable toxicity, and potent antitumor efficacy in vivo against established cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and patient-derived explant (PDE) models. Immunohistochemical analysis of treated tumors demonstrated changes in expression of proliferative marker (ki67, decreased) and the ERS marker (GRP78, increased). These findings support the clinical advancement of ERX-208 for the treatment of patients with OCa.
Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional...Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.
Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molec...Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molecular mechanisms linking inflammation to tumorigenesis are poorly understood. Here, we identify coiled-coil domain-containing 8 (CCDC8) as a potential oncogenic factor in bladder cancer. Transcriptomic analysis revealed that CCDC8 is dysregulated in both IC and bladder cancer, with overexpression confirmed in tumor tissues and cell lines. Elevated CCDC8 expression was significantly associated with advanced tumor stage, lymph node metastasis, and poor prognosis, particularly in patients harboring wild-type TP53. Functional studies demonstrated that CCDC8 promotes tumor cell proliferation, migration, and survival in vitro, and enhances tumor growth in vivo. Mechanistically, CCDC8 interacts with the E3 ubiquitin ligase scaffold protein CUL7, facilitating proteasome-dependent degradation of P53, thereby suppressing its downstream effectors such as P21 and BAX. Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation.
Emerging research highlights the key role of the central nervous system in regulating peripheral tumor progression via neural, neuroendocrine, and immune pathways. Although direct evidence linking the brain to peripheral...Emerging research highlights the key role of the central nervous system in regulating peripheral tumor progression via neural, neuroendocrine, and immune pathways. Although direct evidence linking the brain to peripheral tumor initiation remains limited, recent studies using retrograde tracing have revealed anatomical and functional circuits between specific brain regions and peripheral solid tumors. These circuits influence malignant, stromal, and immune cells within the tumor microenvironment, as well as systemic immune and metabolic processes. In this review, we synthesize current findings on brain-periphery neural networks across multiple cancer types and discuss how tumor burden can reshape brain activity, contributing to emotional and cognitive disturbances, and how the brain, in turn, regulates tumor biology. In particular, we address the translational potential of targeting brain-tumor circuits via neuromodulation, behavioral interventions, and lifestyle-based therapies. Understanding these bidirectional communications offers new approaches for systemic, integrative therapeutic strategies.
Bone metastasis is a devastating complication of non-small cell lung cancer (NSCLC), critically impairing patient survival. Nevertheless, the underlying molecular mechanisms driving this aggressive process remain incompl...Bone metastasis is a devastating complication of non-small cell lung cancer (NSCLC), critically impairing patient survival. Nevertheless, the underlying molecular mechanisms driving this aggressive process remain incompletely elucidated. To systematically investigate these mechanisms, we compared a highly bone-metastatic NSCLC subpopulation with its parental cells. Notably, we identified elevated expression of O-linked β-N-acetylglucosamine transferase (OGT) in the metastatic subpopulation. We further demonstrated that O-GlcNAcylation at the Ser199 site of the nuclear pore protein POM121 is markedly increased and drives NSCLC bone metastasis. Mechanistically, O-GlcNAcylation of POM121 attenuates its interaction with the E3 ubiquitin ligase TRIM21, thus antagonizing ubiquitination and stabilizing POM121. Accumulated POM121 enhances the nuclear import of the oncogenic transcription factor c-MYC. Nuclear c-MYC subsequently orchestrates transcriptional activation of downstream extracellular matrix (ECM)-related genes. Collectively, we elucidate a previously unrecognized OGT-POM121-c-MYC-ECM axis that critically drives NSCLC bone metastasis. Crucially, clinical analysis reveals that high levels of OGT, POM121, and c-MYC positively correlate with adverse clinical outcomes. These findings establish the OGT-POM121-c-MYC-ECM axis as a potential diagnostic biomarker and a promising therapeutic target for NSCLC bone metastasis.
Anaplastic thyroid cancer (ATC) is a highly lethal malignancy characterized by rapid progression and therapeutic resistance. This study uncovers the pivotal role of extracellular matrix (ECM) stiffness in driving ATC agg...Anaplastic thyroid cancer (ATC) is a highly lethal malignancy characterized by rapid progression and therapeutic resistance. This study uncovers the pivotal role of extracellular matrix (ECM) stiffness in driving ATC aggressiveness through mechanotransduction mediated by the Integrin α6β4/Focal Adhesion Kinase (FAK) axis. By engineering collagen-coated polyacrylamide hydrogels with tunable rigidity, we demonstrated that high ECM stiffness (60 kPa) markedly enhanced ATC cell proliferation, clonogenicity, migration, and invasion. Mechanistically, stiff matrices induced cytoskeletal reorganization, activated RhoA/Rac1/Cdc42 signaling, and upregulated Integrin α6β4-FAK pathway components, as validated by transcriptomic, proteomic, and functional assays. Pharmacological inhibition of FAK reversed stiffness-dependent tumor-promoting effects in vitro. In vivo, mice injected with tumor cells pre-cultured on high-stiffness ECM-mimicking hydrogels exhibited accelerated subcutaneous tumor growth and increased lung metastatic burden, which were significantly attenuated by FAK-targeted therapy. These findings establish ECM stiffness as a biomechanical determinant of ATC progression and metastasis, offering novel insights into microenvironment-driven malignancy and highlighting FAK as a promising therapeutic target to disrupt mechanosignaling in ATC.
Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and im...Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and immunohistochemical (IHC) staining of biological samples from patients in the CBCSG010 clinical trial who were randomized to receive adjuvant docetaxel-anthracycline-based chemotherapy with or without capecitabine. We find that patients with a better prognosis in the capecitabine group exhibited an immune-inflamed microenvironment and upregulation of interferon pathways. Moreover, we identify interferon-related TANK-binding kinase 1-binding protein 1 (TBKBP1) as the key gene involved in capecitabine resistance. We uncover that TBKBP1 promotes capecitabine resistance through impairment of activated immune cells infiltration in vivo. Mechanistically, TBKBP1 negatively regulates type I interferon pathway activated by capecitabine treatment, by promoting autophagy-mediated protein degradation of TANK binding kinase 1 (TBK1). In summary, our study implicates TBKBP1 in mediating capecitabine resistance and may serve as a potential therapeutic target for the treatment of TNBC.