Melanoma is one of the deadliest forms of skin cancer and affects tens of thousands of people each year. Although novel targeted and immune therapies have been approved, they often work transiently with resistance eventually ensuing, or are accompanied by significant toxicities. The transcriptional program organized by melanoma drivers is poorly understood. Here we propose to dissect the melanoma metastasis-supportive transcriptional program organized by the transcription factor Heat Shock Factor 1 (HSF1). Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. Our preliminary data indicate that the ubiquitin ligase FBXW7 interacts with HSF1 through a conserved motif phosphorylated by GSK3? and ERK1. FBXW7 is either mutated or transcriptionally down-regulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. We proposed to investigate the molecular basis for FBXW7 silencing in melanoma (Aim 1), and dissect the role of HSF1 in melanoma initiation and progression and the effects of FBXW7 loss or silencing on HSF1 stability by using novel in vivo models (Aim 2). In addition, we will identify the HSF1-regulated transcriptome and examine the in vivo effects of a subset of HSF1 direct targets (Aim 3). Our studies will elucidate the metastasis-supportive transcriptional program orchestrated by HSF1 and its regulation by a tumor suppressor (FBXW7) frequently mutated or silenced and will provide us with novel therapeutic targets for melanoma.

Public Health Relevance

In this project we study the role of the interaction between FBXW7, an E3 ligase frequently mutated or silenced in melanoma, and HSF1, a transcription factor that controls cellular stress responses. We demonstrate that HSF1 is a key regulator of melanoma stress response, induction of metastasis and disease progression. We propose here to further study this interaction using animal modeling and to identify HSF1 transcriptional targets that regulate melanoma metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA202027-04
Application #
9689419
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2016-07-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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