Defining NRF2-independent ROS management as bottleneck to tumor initiation
Worldwide Cancer Research
New York University
Cancer is generally viewed as a genetic disease, which develops when cells acquire mutations in proto-oncogenes and tumor suppressors. These mutations are thought to progressively derail tissue homeostasis, allowing for an expansion of tumorigenic clones with unlimited proliferative potential that fuels long-term tumor growth. Surprisingly, recent mutational analyses of physiologically normal skins unveiled a mutational spectrum and burden that is similar to what had been reported for squamous cell carcinomas (SCCs). Additionally, intravital imaging revealed that skin epithelial progenitor cells (EPCs) with oncogenic mutations persist only transiently and are primarily outcompeted by normal EPCs. These observations, along with stereotypic transcriptional and metabolic changes, which distinguish tumor propagating SCC cells (TPCs) from normal EPCs, suggest that epigenetic adaptation is critical for tumor initiation and persistent expansion. Still, the mechanisms facilitating this epigenetic and metabolic rewiring are largely unknown. Here, we will test the hypothesis that de novo Paired-like homeodomain transcription factor 1 (PITX1) expression facilitates the epigenetic and metabolic reprogramming of KrasG12Dmutant EPC into TPCs. PITX1 dependent changes in chromatin accessibility will enhance self-renewal and increase cell survival by reducing Ras generated reactive oxygen species (ROS). Specifically, we will (1.) determine how PITX1 cooperates with KrasG12Das they reprogram the transposase accessible open chromatin of homeostatic EPCs into the TPC specific epigenetic landscape; (2.) measure how these changes in chromatin accessibility influence ROS management; and (3.) determine if PITX1 dependent antioxidant production is a rate limiting step for tumor initiation. The results of our proposed research are expected to illuminate how oncogenic stress co-operates with sequence specific transcription factors to epigenetically rewire a homeostatic state into a tumorigenic epigenome, which allows TPCs to meet the metabolic demands required for tumor expansion. Once identified, these mechanisms could improve the early diagnosis and prevention of this exceedingly common and deadly human cancer.
1.1 Normal biological development and functioning