Abstract 1502: Cell State Mapping Reveals a Role for a Stress Program in Melanoma

Abstract Transcriptional profiling has revealed a diverse range of cell states in cancer, but the function of these various states remains elusive. Using a combination of zebrafish melanoma modeling and human validation, we have identified a conserved stress-like state that confers intrinsic drug resistance and is associated with poor patient survival. Single cell sequencing of a series of transgenic zebrafish melanoma tumors revealed 3 distinct cell states that correspond to a neural crest, melanocyte or stress-like state. The existence of these 3 states was confirmed using spatial transcriptomics, a method that does not require tissue dissociation or cell sorting. The stress-like state expresses genes such as fos, hsp70 and ubb, proteins which are all required for adaptation to diverse cellular stresses. A transgenic reporter of the stress like state demonstrates that it has higher tumor seeding capabilities compared to non-stressed cells, and confers intrinsic resistance to MEK inhibitors, a commonly used melanoma therapeutic. The stress program can be induced by extrinsic processes such as heat shock, and confers resistance to MEK inhibitors in both zebrafish and human melanomas. Our study identifies a population of stress-like cells that are present from the time of tumor initiation, suggesting that the transcriptional seeds of therapeutic failure are established during the earliest steps of tumorigenesis. Citation Format: Maayan Baron, Mohita Tagore, Miranda Hunter, Isabella S. Kim, Reuben Moncada, Yun Yan, Nathaniel R. Campbell, Richard M. White, Itai Yanai. Cell state mapping reveals a role for a stress program in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1502.