The primary cilium (PC), a ubiquitous microtubule (MT)-based organelle that protrudes from the apical surface of most human cells, is essential for transducing signals required for growth control. Many cancers, including prostate cancer, exhibit near- complete loss of cilia during the early stages of oncogenic transformation. Novel strategies are urgently needed to treat the most aggressive and worst prognosis prostate cancers, the most common cancer and 2nd leading cause of cancer death for men. The host lab data indicate that the hypoxia-induced cleaved form of the mitochondrial outer membrane channel VDAC1 is a critical regulator of both glycolysis and ciliogenesis. This proposal seeks to delineate the molecular mechanisms involved in the cross-talk between metabolic reprogramming and PC in hypoxia in prostate cancer (PCa) models according to the following workpackages (WP): WP1 addresses 1) the relevance of VDAC1 in the interplay between metabolism and ciliogenesis in PCa in hypoxia and 2) the identification of key regulators (i.e key glycolytic enzymes) of both PC signaling and metabolism. WP2 investigates the close proximity between VDAC1 and PC and test the hypothesis that some mitochondria serve as an alternative microtubule organizing center. The structural and molecular determinants required for MT to emanate from mitochondria and their functional relevance in response to hypoxia will be defined. This WP combine state-of-the art expansion microscopy, in vitro and in silico techniques and will benefit of the scientific expertise from both the host lab and my personal networks. WP3 targets the discovery of ligands that bind specifically at the interface of VDAC1 and MT nucleation complexes to disrupt the interaction and confirm the pharmacological relevance of both the target and selected compounds. Drug discovery will be achieved through the supervisor collaborations with academic and industrial partners.
Call for proposal
See other projects for this call