Elucidating the stress response regulatory networks that enable malignancy

Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the heat-shock response, is a powerful enabler of carcinogenesis. HSF1 is activated in tumors of diverse origin, in a manner that is distinct from its activation during heat-shock. In addition to its role in tumor cells, HSF1 plays a role in the transcriptional reprogramming of nonmalignant stromal cells from a tumor-repressive to a tumor-promoting state. We will use HSF1 as a paradigm for understanding how stress response transcription factors encode information (how HSF1 activation is altered depending on type of stress), decode information (how HSF1 activation state affects its transcriptional program), and affect phenotype (how HSF1 transcriptional programs affect cell state). I will address the following aims during my initial independent research career: 1) Identify and characterize factors that modulate HSF1 activity in cancer. We will use biochemistry and genomic approaches in cell culture and animal models identify and characterize modifiers of HSF1-associated tumorigenesis. 2) To determine, at the molecular level, how HSF1 produces its distinct transcriptional responses in cancer. How HSF1 drives highly divergent transcriptional programs depending on cellular context is unknown. We will use biochemistry and chemical biology approaches to determine the molecular basis for these distinct transcriptional responses. (3) To determine how HSF1 activation contributes to poor clinical response. One possibility is that HSF1 directly regulates genes that enable or promote invasion and metastasis. However, a second, non-mutually exclusive possibility is that HSF1 either affects the sensitivity of cancer cells to therapeutics or enables the emergence of drug resistance. (4) To determine how HSF1 targets contribute to HSF1-mediated phenotypes. We will use CRISPR-Cas9 genome engineering and other approaches to determine the molecular basis for HSF1 phenotypes. The results of these studies will provide a holistic understanding of the operating principles that enable HSF1 to sense diverse cellular stresses and drive diverse transcriptional programs and phenotypes.