Oncogenesis最新文献

Inhibitors that target the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint pathway have revolutionized cancer immunotherapy; however, many patients exhibit a limited response. In this study, we examined the potential of teriflunomide (TER), an FDA-approved drug for multiple sclerosis, as a novel immune checkpoint modulator for treating colorectal cancer (CRC). We determined the effect of TER on PD-L1 expression in human CRC cell lines, its direct binding to PD-1, and its impact on CD8⁺ T-cell function. Antitumor activity was determined in vivo using a humanized mouse model of hPD-1 knock-in mice implanted with hPD-L1 expressing MC38 tumor cells. TER treatment reduced PD-L1 expression in CRC cells and disrupted the PD-1/PD-L1 interaction directly. In vivo, TER significantly suppressed tumor growth without systemic toxicity, and enhanced the infiltration and activation of CD8⁺ T cells within tumors, as evidenced by increased granzyme B expression. Moreover, the antitumor efficacy of TER was abolished by the depletion of CD8⁺ T cells, which indicated its dependency on this cell population. These findings highlight TER as a promising immune checkpoint modulator that targets the PD-1/PD-L1 axis to promote CD8⁺ T-cell-mediated antitumor immunity. Because of its established safety profile, TER is a readily translatable therapeutic for enhancing cancer immunotherapy in CRC.

Accumulating evidence indicates that mitochondrial dynamics are closely linked to the biological behaviors of tumor cells, with increased mitochondrial fission being recognized as a phenotype that promotes tumor growth. Although intermediate filament family orphan 1 (IFFO1) has been implicated in mitochondrial dynamics, its specific role and molecular mechanisms in regulating mitochondrial fission during breast cancer (BC) progression remain unclear. In this study, analysis of tumor and adjacent normal tissues from 30 BC patients revealed significant downregulation of IFFO1 in tumor tissues, and low IFFO1 expression predicted poor prognosis in patients. In vitro experiments demonstrated that IFFO1 overexpression suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of BC cells by inhibiting mitochondrial fission and fatty acid synthesis. Mechanistically, IFFO1 interacts with LaminA/C to promote its expression, which subsequently upregulates PGC1α, thereby suppressing mitochondrial fission and fatty acid synthesis in BC cells. Consistent with this mechanism, both LaminA/C and PGC1α were downregulated in BC tissues. Silencing LMNA reversed the inhibitory effects of IFFO1 overexpression on mitochondrial fission and fatty acid synthesis, whereas overexpression of PGC1α effectively counteracted the consequences of LMNA knockdown. In vivo studies confirmed that upregulation of IFFO1 inhibited tumor growth in xenograft models and reduced lung metastasis in a lung metastasis mouse model. These findings underscore the significance of the IFFO1/LaminA/C/PGC1α pathway as a key regulator of mitochondrial fission and fatty acid synthesis during BC progression and highlight its potential as a therapeutic target for breast cancer.

Lung adenocarcinoma, the predominant type of non-small cell lung cancer, is associated with poor survival outcomes due to late-stage diagnosis, resistance to therapy, and lack of effective metabolic-targeted strategies. Increased glycolysis is a hallmark of LUAD progression, yet the upstream transcriptional and post-translational regulators of glycolytic enzymes remain incompletely defined. This study aims to clarify the molecular mechanisms through which transcription factors and ubiquitin ligases coordinate glycolytic activation and tumor progression in LUAD. We identified ZBTB7B as a transcriptional activator of the non-canonical glycolytic enzyme ADPGK. ZBTB7B expression was significantly increased in LUAD tissues and cell lines, associated with poor prognosis, and enhanced proliferation, migration, and glycolytic flux in an ADPGK-dependent manner. Mechanistically, the E3 ubiquitin ligase NEDD4 directly interacted with ZBTB7B, mediating its ubiquitination at K450 and proteasomal degradation, thereby suppressing ADPGK expression and glycolysis. NEDD4 overexpression suppressed LUAD growth both in vitro and in vivo, effects that were reversed by ZBTB7B restoration. Collectively, this work reveals a novel NEDD4/ZBTB7B/ ADPGK axis that integrates transcriptional and post-translational regulation of glycolysis, offering potential therapeutic targets for metabolic intervention in LUAD.

Intestinal adenomas are premalignant lesions that develop into colorectal cancer (CRC), yet the metabolic pathways underlying their malignant transformation remain poorly characterized. Using targeted metabolomics via ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we found that serum levels of the bioactive lipid metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET) were dramatically elevated in Apc^Min/+ adenoma model mice as early as pre-adenoma stages, compared to C57BL/6 controls. The results were also consistent in adenomas and CRC patients. ELISA data and bioinformatics analyses revealed both elevated serum 14,15-EET levels and upregulated cytochrome P450 2J2 (CYP2J2) expression in tumor. Functional studies showed that 14,15-EET accelerates adenoma growth in vivo, and promotes proliferation, migration, and invasion in vitro by activating AKT (Ser473)/ERK1/2 signaling and inducing epithelial-mesenchymal transition (EMT). Its early elevation in premalignant lesions, and relative molecules 14,15-EET/CYP2J2 represents a novel strategy for disrupting adenoma-carcinoma transition, and offering new biomarker for CRC prevention.

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The prognosis of the metastatic cSCC is poor, and there are no established biomarkers to predict metastasis risk, nor specific targeted therapies for advanced or metastatic cSCC. Previous studies have demonstrated that the complement serine proteinase C1s promotes cSCC growth both in culture and in vivo by modulating apoptotic signaling. Here, we investigated the mechanistic role of C1s in regulating apoptosis by examining its impact on cell surface proteome of cSCC cells. Mass spectrometric analysis of cell surface proteins following silencing of C1s identified TRAIL receptor 1 (DR4) as a candidate target, showing increased accumulation at the cell surface. This finding was validated using cell surface biotinylation and western blot analysis in both siRNA-mediated C1s knockdown and CRISPR/Cas9-generated C1s knockout cells. Functionally, high endogenous levels or forced overexpression of C1s conferred resistance to TRAIL-induced apoptosis in cSCC cells, whereas reduced C1s levels sensitized cells to apoptotic signaling. These findings suggest that upregulation of complement C1s in cSCC not only contributes to tumor progression but also serves as a protective mechanism against TRAIL-induced apoptosis, highlighting its potential as a therapeutic target and biomarker in aggressive cSCC.

High-risk human papillomavirus (HPV) is a causal factor in cervical cancer, driving the cancer's initiation and progression. Although cancer stem cells (CSCs) have been implicated in maintaining the stemness and malignancy of cervical cancer cells, the underlying mechanisms are not yet fully understood. In this study, we modulated gene expression in Caski and SiHa cervical cancer cells using siRNA and overexpression approaches. Functional assays, including MTT, transwell, RT-qPCR, western blotting, immunohistochemistry, luciferase reporter, immunofluorescence, and sphere formation, were performed to evaluate target gene expression. Additionally, transcriptome sequencing was used to analyze the impact of silencing HPV16 E7 on SiHa cells, and a xenograft model was assessed for in vivo effects. Our transcriptome sequencing reveals substantial changes in gene expression profiles upon HPV16 E7 silencing in cervical cancer. Notably, we identified APC2 as a key downstream target transcriptionally activated by HPV16 E7 through the transcription factor E2F1, and its elevated expression is associated with poor prognosis in cervical cancer. Surprisingly, APC2 exhibits oncogeneic properties in cervical cancer by activating the Wnt/β-catenin pathway, and its overexpression reverses the inhibitory effects of HPV16 E7 silencing on malignancy and CSC properties. Additionally, SPIN4 is identified as a pivotal downstream target of the HPV16 E7/APC2 axis, positively modulating cervical cancer progression. Our study reveals a novel HPV16 E7-APC2-SPIN4 axis as a key driver of cervical cancer. In this pathway, APC2 unexpectedly functions as an oncogene by activating the Wnt/β-catenin signaling to promote tumorigenesis and CSC properties.

Cancer metastasis is the leading cause of cancer-related death. While organs such as the lung are hotspots for metastases, others -like skeletal muscle- remain rarely colonized, a phenomenon that remains poorly understood. In this study, we show that EO771 breast cancer cells proliferated robustly when co-cultured with MLg lung stromal cells, whereas their proliferation was restrained when maintained in direct contact with differentiated C2C12 skeletal muscle myotubes. Notably, these effects were not cell-type-specific, as similar results were obtained with 4T1 breast cancer cells and Sol8 myotubes. After two days of co-culture, both cancer and host cells (MLg and C2C12) exhibited distinct niche-specific transcriptional remodeling. Strikingly, the poorly proliferative EO771 cells co-cultured with C2C12 myotubes acquired a hypoxia-associated gene-expression signature despite normoxic conditions (~20% O₂), showing that muscle cells reprogram cancer cells into a hypoxic, anti-proliferative state. Under hypoxic conditions, we confirmed that the depletion of oxygen allows C2C12 cells to nearly abolish EO771 proliferation. Neither exogenous lactate, culture acidosis, their combination, altered glucose levels, nor conditioned medium could reproduce the suppressive environment created by C2C12 myotubes. In contrast, MLg cells induced minimal transcriptional changes in EO771 cells and were themselves broadly reprogrammed by the cancer cells. Moreover, hypoxia enhanced EO771 proliferation in MLg co-cultures, emphasizing the permissive nature of the MLg environment. Collectively, these findings uncover a unique, paradoxical, muscle-induced pseudo-hypoxic program that restricts cancer cell proliferation. They also highlight the need for caution in targeting hypoxia signaling in anti-metastatic therapies, as such interventions could weaken skeletal muscle's natural defense against tumor colonization.

T cell senescence significantly impairs the efficacy of immune checkpoint blockade (ICB) therapy in cancer. Metabolic reprogramming is a crucial factor in T cell senescence in tumor microenvironment (TME). Ovarian cancer (OvCa) patients derive limited benefit from ICB treatment, probably related to T cell senescence. OvCa cells metastasize to the abdominal cavity rich in omental fat and raise ascites, forming a unique TME, adipocyte-rich TME. In this study, we investigated the effects of adipocyte-rich TME on T cell senescence. Using the single-cell RNA sequencing of OvCa and clinical samples, we found that adipocyte-rich TME is strongly associated with the formation of senescence CD8⁺T (CD8⁺Tsen) cells. Mechanistically, adipocyte-derived factors (MATES) and oleic acid (OA)-the predominant fatty acid in OvCa ascites-promoted tumor-induced CD8⁺Tsen formation by enhancing fatty acid (FA) uptake via FABP4, triggering lipid peroxidation rather than energy production. Inhibition of FABP4 (using the inhibitor BMS309403 or siRNA knockdown) blocked CD8⁺Tsen cell formation, reduced lipid peroxidation, restored CD8⁺T cell effector function, and suppressed immunosuppressive cytokines. Moreover, using an OvCa mouse model, we found that in OvCa mice BMS309403 treatment partially diminished CD8⁺Tsen formation by reducing FA uptake, and improved anti-tumor immunity, and prolonged the survival time of OvCa mice when combined with chemotherapy. Our work suggests FABP4-mediated FA metabolism as a therapeutic target to counteract T cell senescence in adipocyte-rich TME, providing a novel immunotherapeutic strategy for OvCa.

Colorectal cancer (CRC) cell lines represent the main molecular subtypes of tumors and are valuable models for preclinical investigations. However, cell lines can diverge over time and careful selection of models based on their molecular features is key. We have authenticated 103 commonly used CRC cell lines and present the mutation profiles of 20 CRC-relevant genes sequenced to an average depth of 575 times coverage. The cell lines reflected the distinct mutation patterns of hypermutation phenotypes associated with microsatellite instability and pathogenic POLE mutations. Hypermutated cell lines appeared to have a stronger mutational divergence and more frequent subclonal mutations, while mutations not associated with hypermutation were more frequently homozygous or hemizygous, classified as pathogenic, and subject to stronger selection pressure. Loss of heterozygosity at mutated loci was primarily observed in tumor suppressor genes. Genetic interactions based on co-occurring mutations identified cell lines representative of particularly aggressive subtypes of CRC, including concurrent BRAF p.V600 and truncating APC mutations, as well as APC/TP53/RAS triple mutations with double hits of APC. This study provides a resource to guide the selection of cell lines for functional studies of CRC, and detailed mutation data including classifications of pathogenicity, variant allele frequencies and illustrations of the mutation distribution along the length of encoded proteins are included.