Oncogenesis最新文献

Cytoskeletal network dynamics play important roles in regulating cellular functions. Although alterations in cytoskeleton-related genes are frequently detected, limited attention has been paid to their roles in cancer development. A novel keratin fusion variant, K6-K14/V5, was previously identified in head and neck squamous cell carcinoma (HNSCC), and its expression led to catastrophic nuclear collapse, resulting in DNA breaks and cGAS-STING activation. Such cell-killing effects can trigger autophagy induction, which, in turn, promotes cancer cell evolution/clonal selection in a dormant state. Furthermore, due to the disrupted cellular architecture and the loss of mechanosensing, these dormant cells could survive and adapt within a collagen gel. Upregulation of the partial epithelial-mesenchymal transition (pEMT) program by cytoskeleton reorganization was defined as a key step for these dormant cells to reactivate and regain their mechanical properties. Striking cell protrusions and increased MMPs were observed in the reactivated cells, facilitating the interaction with the surrounding extracellular matrix and enhancing their invasive potential. Elevated extracellular vesicles were detected in the reactivated cells, which actively stimulated tumor growth via the FGF-FGFR axis. Our study therefore offers a novel model for understanding how genetic alterations in cytoskeletal genes can directly contribute to cancer development and drive cancer evolution.

Hepatocellular carcinoma is a devastating malignancy with numerous therapeutic targets to guide treatment strategies against the disease. However, given the limited efficacy of current frontline targeted therapies in prolonging the survival for HCC patients both as single agents and in combination, evaluating the potential of epigenome remodelling as a therapeutic target opens unexplored avenues for the clinical management of HCC. In this study, we identified epigenetic vulnerabilities to expand the repertoire of therapeutic strategies for HCC patients. To identify epigenetic regulators essential in HCC, we integrated the functional responses of six HCC cell lines to genetic perturbation of epigenetic regulators using esiRNA with existing data from publicly available databases. Correlation between phenotypic responses of HCC cells to large-scale genetic knockdown of epigenetic regulators and publicly available datasets narrowed down the pool of epigenetic vulnerabilities in HCC to two prospective epigenetic oncogenes (SUPT7L and SMARCC1) and one prospective epigenetic tumour suppressor (PHF2). Subsequently, PHF2 loss-of-function studies in HCC cells were performed through functional, molecular and proteomic analyses. Deeper investigations into PHF2 further established its functional role in mitigating cancer cell growth in vitro. Molecular and proteomic analyses in PHF2-deficient cells further suggested that PHF2 functionally suppresses cancer growth in part through the regulation of the cytoprotective protein, SRXN1. Further characterisation of PHF2-deficient cells were suggestive of independence from the Keap1-Nrf2 pathway. Collectively, our study suggests that PHF2 acts as a candidate epigenetic tumour suppressor in HCC patients through the downregulation of SRXN1, potentially independent of Nrf2.

Tumor-associated Macrophages (TAMs) are highly plastic immune cells that shape the tumor microenvironment (TME) and influence cancer progression. However, the molecular determinants governing their functional heterogeneity remain incompletely understood. In this study, we identify Rab37 as a key regulator that remodels the states of macrophages within the lung TME. Single-cell RNA sequencing revealed that Rab37 wild-type (WT) tumors were enriched in immunosuppressive Spp1⁺ TAMs, whereas Rab37 knockout (KO) tumors contained a higher proportion of Thbs1⁺ TAMs, suggesting Rab37-dependent shifts in macrophage programming. Mechanistically, Rab37 promoted osteopontin (OPN) secretion, which activated STAT3 signaling to establish an autocrine feedback loop that sustained Spp1 expression and induced M2-like polarization. Paracrine OPN signaling further enhanced lung cancer cell proliferation, migration, and invasion. In clinical lung cancer specimens, CD163⁺/Rab37⁺/OPN⁺ TAMs correlated with recurrence and poor survival, and multivariate analysis confirmed their independent prognostic value. Together, these findings demonstrate that Rab37 governs macrophage phenotype and function by orchestrating OPN/STAT3 signaling, thereby reinforcing an immunosuppressive TME and promoting lung cancer progression. Targeting the Rab37-OPN axis may thus represent a promising therapeutic strategy.

Iron enables tumor cells to maintain pro-tumoral functions including DNA synthesis and repair, drug resistance and metabolic processes such as oxidative phosphorylation and regulation of reactive oxygen species. To meet these demands, tumor cells rewire iron metabolism to increase iron uptake and use. Therefore, disrupting iron metabolism either by limiting availability or by exploiting iron accumulation to induce ferroptosis, might be a promising strategy for cancer therapy. Recent studies suggest that other cell populations in the tumor microenvironment, including immune cells and cancer-associated fibroblasts, depend on iron and can contribute to iron dysregulation in tumors. Here, we will discuss how iron-dependent pathways contribute to tumor development, with a focus on iron sulfur cluster proteins and heme and their effects on metabolism. In addition, we will describe the relevance of iron crosstalk within the tumor microenvironment in promoting tumor growth, metabolic reprogramming and immune evasion. Finally, we will explore the therapeutic potential of targeting iron-dependent processes beyond the scope of ferroptosis.

Cancer stem cells (CSCs) play a pivotal role in driving colorectal cancer (CRC) progression and therapeutic resistance. However, the molecular mechanisms regulating CRC-CSC properties are not fully understood. Proline-rich Akt substrate 40 (PRAS40) is involved in various tumorigenic processes, yet little is known about its contribution to cancer stemness. In this study, we demonstrated that PRAS40 was overexpressed in CRC tissues and its elevated expression positively correlated with poor patient survival. Genetic ablation of PRAS40 suppressed tumorigenesis in CRC mouse models. Notably, PRAS40 enhanced the stemness of CRC cells, as evidenced by increased sphere formation, upregulation of stem cell markers, enrichment of the CD133⁺CD44⁺ cell population, and enhanced tumor initiation capacity in vivo. Mechanistically, PRAS40 induced a glycolytic phenotype by interacting with and activating the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Furthermore, PRAS40 enhanced the interaction between PGK1 and the acetyltransferase p300/CBP-associated factor (PCAF), thereby promoting PGK1 acetylation, which contributes to glycolysis activation and the maintenance of CRC stemness. Pharmacological inhibition of acetylation attenuated PRAS40-mediated CRC stemness and colorectal carcinogenesis. Collectively, our findings uncover a novel PRAS40/PGK1 regulatory axis that promotes CRC stemness and tumorigenesis through enhanced glycolysis, suggesting potential therapeutic strategies targeting this axis for CRC treatment.

Although the FOLFOX strategy has demonstrated benefits for tumor patients at advanced stages, chemoresistance remains a significant challenge to therapeutic efficacy. Thus, identifying strategies to overcome chemoresistance and enhance chemotherapy sensitivity is critical for optimizing HAIC-FOLFOX treatment. Comprehensive investigations of deubiquitinating enzymes (DUBs) across multiple bioinformatics cohorts and a local hepatocellular carcinoma (HCC) cohort identified ubiquitin-specific protease 1 (USP1) as a key regulator of HCC progression, correlating with poor survival outcomes. Functional assays demonstrated that USP1 overexpression promotes aggressive phenotypes in HCC cells, including enhanced proliferation, migration, and epithelial-mesenchymal transition (EMT), whereas USP1 inhibitor ML323 suppresses these effects and increases sensitivity to oxaliplatin and fluorouracil (5-FU), the primary agents in FOLFOX, both in vitro and in vivo. Mechanistic studies revealed that USP1 interacted with and stabilized the chromatin-remodeling factor lymphoid-specific helicase (HELLS) through deubiquitinating, thereby facilitating EMT and homologous recombination repair (HRR), thereby driving chemoresistance. Furthermore, USP1 promoted HELLS SUMOylation by stabilizing PIAS1, an E3 SUMO ligase, through deubiquitination and prevention of its ubiquitin-mediated degradation. Importantly, inhibition of SUMOylation significantly attenuated the aggressive effects mediated by USP1. In conclusion, this study highlights the USP1/PIAS1/HELLS deubiquitinating and SUMOylation axis as a critical driver of aggressiveness and DNA damage repair responses in HCC cells, offering a promising therapeutic strategy to suppress HCC progression and enhance the efficacy of FOLFOX-based chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial oxidative metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzed ex vivo by flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, bulk RNA-sequencing and RT-qPCR. We show increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. These metabolic features are also observed in tumors during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that metabolic adaptations occurring during treatment-induced regression may favor the survival of drug-tolerant persister (DTP) cells, which persist during the subsequent minimal residual disease and are responsible for cancer relapse. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, redox metabolism is a vulnerability of pancreatic DTP cancer cells that can be targeted to prevent relapse.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

Tetraspanins are transmembrane proteins that organize into functional structures known as tetraspanin-enriched microdomains, where they coordinate interactions with key partner proteins and modulate cellular processes such as adhesion, signaling, and motility. Among them, CD9 is a widely expressed member, also recognized as a classical marker of exosomes. Beyond its role in development and tissue homeostasis, CD9 has emerged as a modulator of the crosstalk between cancer cells and their microenvironment. It can contribute to processes such as cell migration, invasion, and resistance to therapy. Mechanistically, CD9 interacts with many partners including integrins, metalloproteinases, and signaling receptors to influence cell behavior. However, its functional contribution to tumor progression remains controversial. While CD9 expression is associated with enhanced dissemination in certain cancers, it appears to restrain motility and invasion in others. This likely reflects the complexity of its context-dependent functions, influenced by cell type, microenvironmental cues, and molecular partners. A deeper understanding of the regulatory mechanisms is therefore essential. In this review, we overview the tetraspanin family and summarize current knowledge on CD9 regulation and function across cancers, with a focus on leukemia. While its role in tumorigenesis remains debated, CD9 is a reliable biomarker of leukemic cells and can be used for diagnosis and MRD monitoring in acute lymphoblastic and myeloid leukemia, particularly in patients lacking molecular markers. We also discuss emerging therapeutic strategies that aim to target CD9 in cancer. CD9 gene regulation in cancer, and biological implication in acute lymphoblastic leukemia. Created with BioRender.com.

The deubiquitinating enzyme Ubiquitin specific peptidase 5 (USP5) has attracted substantial notice for its vital role in cancer progression. However, the USP5-mediated deubiquitination of corresponding protein substrates and its functional role in hepatocellular carcinoma (HCC) have not been fully investigated. Here, we demonstrated that USP5 expression was significantly elevated in HCC tissues. The overexpression of USP5 was closely associated with larger tumor sizes, more satellite nodules and tumor emboli, and predicted unfavorable clinical outcome in HCC patients as well. Functionally, USP5 facilitated cell proliferation, migration, and invasion, and induced lipid accumulation in vitro, along with enhanced tumor growth in vivo. Moreover, knockdown of USP5 expression showed a profound effect on lipidomic profiling, specially reduced the content of palmitic acid (PA). Treatment of PA could partially rescue the suppression of HCC mediated by USP5 knockdown. Further mechanistic investigation uncovered that Fatty acid synthase (FASN), the crucial enzyme catalyzing PA synthesis, was a downstream target of USP5. USP5 interacted with FASN, repressing the ubiquitination modification of FASN and preventing its degradation. Notably, the positive correlation between USP5 and FASN expression in HCC tissues was observed, and USP5 exerted oncogenic effects partly via FASN. Our findings revealed that USP5 promotes HCC progression through deubiquitinating FASN, and targeting the USP5-FASN-PA axis could potentially serve as a strategic approach for the therapy of HCC.