Chiara, M.-D. | bioRxiv Science

bioRxiv2024

PCDHGC3 silencing promotes renal carcinoma metastasis via mTOR/HIF2a and lipid metabolism rewiring

Clustered protocadherins (cPCDH) are widely expressed in the nervous system with known functions, but their roles in cancer, particularly metastasis, are largely unexplored. Our previous research revealed that epigenetic silencing of PCDHGC3 is linked to decreased survival in neuroendocrine cancer patients. This study investigates PCDHGC3s role in clear cell renal cell carcinoma (ccRCC). We found that decreased PCDHGC3 expression is associated with lower survival and advanced disease stage in ccRCC patients. shRNA-mediated PCDHGC3 silencing in renal cancer cell lines significantly increased cell proliferation, invasion, and survival. In orthotopic mouse models, PCDHGC3 silencing promoted metastasis. The mTOR and HIF2 pathways were identified as downstream targets activated by PCDHGC3 loss. Inhibition of these pathways counteracted the effects of PCDHGC3 silencing, highlighting their importance in tumor progression. Proteomic and metabolomic analyses showed that PCDHGC3 silencing led to overexpression of proteins involved in fatty acid and cholesterol synthesis, increasing lipid droplets and shifting lipid metabolism. This metabolic reprogramming characterizes aggressive ccRCC. Our study emphasizes PCDHGC3s impact on ccRCC metastasis and suggests mTOR or HIF2 inhibitors as potential therapies for PCDHGC3-deficient patients.

cancer biology↗

bioRxiv2021

Identification of a minimal biomarker profile in head-and-neck squamous cell carcinoma tumors

Although important advances have been made in the knowledge of the molecular mechanisms leading to the development, of head and neck squamous cell carcinoma (HNSCC), only PDL1 is used for the immunotherapy (pemborlizumab) treatment in the first line of metastatic or recurrent disease. There are no other molecular biomarkers currently used in clinical practice. The objective of the study was to identify transcriptional alterations in patients with oral cavity cancer that identify gene networks responsible for resistance to treatment and prognosis. To identify possible targets for the treatment or prevention of these tumors, we screened for changes in transcription of genes that were recurrently altered in patients and that successfully stratify tumoral and non-tumoral samples, as well as patient survival, based on expression levels. The gene panels are primarily related to the cell cycle, DNA damage response, cytokine signaling and the immune system but also to the embryonic stem cell core. Validation of these panels in an independent cohort led to the identification of three non-interconnected genes, WDR66, SERPINH1 and ZNF622, that can predict patient survival and are differentially expressed in 3D cultures from HNSCC primary cell lines. These genes are related to stemness phenotype are transcriptional targets of the pluripotency transcription factors Sox2 and c-Myc. Our results suggest that WDR66, SERPINH1 and ZNF622 con-stitute a minimal signature of stemness transcriptional targets able to predict the prognosis of HNSCC tumors. Simple SummaryThe objective of the study was to identify transcriptional alterations in patients with oral cavity cancer to possibly identify gene networks responsible for resistance to treatment and prognosis. We identify bioinformatically gene panels are primarily related to the cell cycle, DNA damage response, cytokine signaling and the immune system but also to the embryonic stem cell core. Validation of these panels in patients independent cohorts led to the identification of three non-interconnected genes, WDR66, SERPINHl and ZNF622, that can predict patient survival and are differentially expressed in cancer stem cells cultures from HNSCC. These genes are related to stemness phenotype and epithelial-to-mesenchymal transition and are transcriptional targets of the pluripotency transcription factors Sox2 and c-Myc.

cancer biology↗