In previous work we demonstrated that Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the heat-shock response, is a powerful enabler of carcinogenesis. My previous studies establish that HSF1 operates in cancer in ways that are fundamentally distinct from the heat-shock response. In multiple cancers, the HSF1 cancer program is activated and is strongly associated with metastasis and death. The molecular mechanisms responsible for the distinct HSF1 activation state that enables highly malignant cancers remain enigmatic. To define these mechanisms, I will pursue the following aims during the remaining years of mentored training and as I start my independent career: (I) Define the key signal transduction pathways that activate HSF1 in cancer. HSF1 is activated in cancers of diverse origin. How HSF1 is activated in cancer is largely unknown. To define these mechanisms, I will employ a systematic approach using state-of-the-art technologies. I will integrate these data to define the signaling mediators used by the different oncogenic, environmental and endogenous stressors that activate HSF1. (II) Determine how HSF1 produces its distinct transcriptional response in cancer. The transcriptional program HSF1 coordinates in cancer is distinct from that in response to heat-shock. The molecular mechanism responsible for the differences in HSF1 gene occupancy in cancer vs. heat-shock is unknown. I will use mass spectrometry, biochemistry and other methods to determine the molecular basis for this distinct transcriptional response. (III) Determine how HSF1 activation contributes to the poor clinical response.The mechanisms underlying this phenomenon have immense relevance to cancer diagnosis and treatment. One possibility is that HSF1 enables a more malignant phenotype. A second, and non-mutually exclusive possibility is that HSF1 potentiates the emergence of drug resistance. I will use both an in silico approach, based on recently released, publically available data and an experimental approach, based on access to a unique clinical resource through a collaboration. Understanding the regulatory hub of the HSF1 network and how its activation enables a particularly aggressive type of malignancy is of immense clinical importance.
While an immense catalogue of oncogenic mutations offers myriad to dive malignancy, the dependence on the proteostasis network is emerging as a unifying hallmark of cancer. Understanding the regulatory hubs of this network is of immense clinical importance and targeting these hubs offers a powerful therapeutic strategy. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|Tsvetkov, Peter; Mendillo, Marc L; Zhao, Jinghui et al. (2015) Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome. Elife 4:|
|Scherz-Shouval, Ruth; Santagata, Sandro; Mendillo, Marc L et al. (2014) The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158:564-78|
|Whitesell, Luke; Santagata, Sandro; Mendillo, Marc L et al. (2014) HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models. Proc Natl Acad Sci U S A 111:18297-302|