Celada, L. | Search bioRxiv

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↗

bioRxiv2024

Convergent genetic adaptation in human tumors developed under systemic hypoxia and in populations living at high altitudes

EPAS1HIF2 is the primary gene implicated in systemic hypoxia adaptation. Conversely, aberrantly activated EPAS1HIF2 acts as a tumor driver against which anti-tumor therapeutics are proven effective. We elucidated connections between adaptation to systemic hypoxia in high-altitude populations, such as Tibetans and Sherpas, and human tumors. Similar to the accelerated adaptability observed in high-altitude populations via genetic introgression, tumors from patients with hypoxia since birth exhibited impaired DNA repair and increased mutation burden. As in high-altitude dwellers, EPAS1HIF2 genetic variants were positively selected within sympathetic tumors developed under hypoxia, with a consistently high frequency of 90%. Bulk and single-cell RNA sequencing followed by in vitro studies have shown that hypoxia and EPAS1HIF2 gain-of-function tumor mutations induce COX4i2 expression and impair mitochondrial respiration, indicating that decreased cellular oxygen consumption may confer a proliferative advantage in hypoxia. Analyzing medical data from a patient cohort with hypoxia since birth who developed/did not develop tumors revealed tissue-specific and time-dependent tumorigenic effects of systemic hypoxia, which is limited to oxygen-sensitive and responsive cells, particularly during the postnatal period. This study supports connections between the EPAS1HIF2 genetic adaptation in human tumors developed under systemic hypoxia to populations living in high altitudes. The genetic adaptations in populations to different stressors can be explored further to understand tumorigenesis and tumor evolution.

cancer biology↗