Genetic and pharmacological targeting of epigenetics regulators in cancer stroma prevents/suppresses skin cancer.
Background & Significance
Stromal fibroblasts are connective tissue cells found in any organ. The conversion of stromal fibroblasts into cancer-associated fibroblasts (CAFs), and the associated chronic inflammation can play a primary role in cancer initiation and progression. This is relevant for field cancerization, a condition of major clinical significance consisting of multiple and recurrent pre-malignant and malignant tumours in many organs, including skin, head/neck, lung, breast, prostate and colon. This condition is very difficult to treat and greater insights into how it develops are urgently needed.
We have shown that controlling the CAF activation leads to changes that can be overcome by treatment with inhibitors of specific determinants of the epigenome, which, at the same time, induce differentiation of adjacent cancer cells. Importantly, treatment of CAFs with these drugs also induces activity in the androgen receptor (AR), which by itself is sufficient to revert CAF activation. This project focuses on the convergent role of a) drugs targeting non-genetic causes of cancer and b) the factors that influence AR activity towards suppressing CAF activation and skin cancer development and expansion.
Training to an ESR on the impact of genetic and pharmacological targeting of Brd proteins on incidence and progression of skin cancer (SCC and melanoma). The ESR has to
compare the impact of specific silencing of the Brd1-4 genes vs treatment with chemical Brd inhibitors on CAF activation;
assess the impact of AR agonists and antagonists on the same cells as well as neighbouring SCC and melanoma cells;
probe into underlying mechanisms by comparative transcriptomic analysis of multiple CAF and SCC and melanoma strains plus/minus treatment with the two classes of chemical compounds;
evaluate the impact of topical and systemic treatment with these compounds on skin SCC and melanoma formation, utilizing an orthotopic ear injection assay in immune competent mice, to take into consideration the role of the immune system.
Enrolment in Doctoral degree(s):
- University of Lausanne