(3) Interplay between androgen receptor (AR) signaling, cancer associated fibroblast activation and skin cancer development.

HYPOTHESIS

Loss of AR signaling promotes cancer associated fibroblast activation (CAF) activation and skin cancer development.

Background & Significance

Males face significantly higher rates of cancer in non-reproductive organs, than females. This is the result of a complex interplay between a) sex hormones and b) the genetic factors that predispose people to cancer, control stromal cells around them and organismic functions (immune system and metabolism). With age, the levels of male sex hormones (androgens) vary substantially in individuals of the two sexes, and may contribute to the exponential increase of many cancer types associated with aging. The conversion of stromal fibroblasts into cancer-associated fibroblasts (CAFs) plays a key role in the initiation and the progression of various forms of skin cancer, including melanoma. This project focuses on the role that androgen receptors (AR) play in signalling changes in stromal fibroblast and melanoma cells taking a global transcriptomic / bioinformatic approach. The research will provide a benchmark of major clinical significance to study the complex interplay between sex- and aging-associated cancer risk.

Objectives

Ongoing studies in the lab indicate that AR expression is down-modulated in dermal fibroblasts of photo-aged skin and underlying premalignant skin cancer lesions (actinic keratoses, AK) and is similarly reduced in CAFs from major skin cancer types, SCC and melanomas19. Building on these findings, the objective is to provide training to an ESR on the role of AR in epigenetic / transcriptional control of CAF activation and resulting impact on skin cancer development. The ESR has to assess

the functional consequences of AR gene silencing on in vitro properties of primary human dermal fibroblasts (HDFs);

the impact of HDFs plus/minus AR knock-down on skin SCC and melanoma development in an orthotopic mouse model of the diseases;

perform transcriptomic and AR ChIP-seq analysis to identify genes with CAF effector functions under direct AR control;

integrate the transcriptomic results with mRNA expression profiles of skin from identical and di-zygotic twins to identify patterns of androgen responsive genes in the stroma that can be linked to high versus low skin cancer risk.

Enrolment in Doctoral degree(s):

  • University of Lausanne