Abstract 278: Aerobic exercise suppresses melanoma tumor growth via upregulating ERK5 S496 phosphorylation
Authors: Savage Hannah , Pareek Sumedha , Lee Jonghae , Ballaro Riccardo , Samanthapudi Venkatasubrahman , Ko Kyung Ae , Imanishi Masaki , Kotla Sivareddy , Abe Jun-ichi , Schadler Keri 
Published: June 2022

Abstract
Hypoxia, immune cell infiltration, and drug delivery are key elements of therapeutic efficacy in solid tumors. Each are strongly influenced by the tumor microenvironment. Identification of novel methods to change the microenvironment is needed to improve the response of solid tumors, including melanoma, to therapies like immune checkpoint blockade. We and others have demonstrated that aerobic exercise remodels tumor microenvironment in multiple tumor types. Here, we present data to suggest that this exercise-induced remodeling of the tumor microenvironment is partially dependent on modulation of ERK5 in both tumor endothelium and infiltrating immune cells. The depletion of ERK5 in tumor-associated macrophages inhibits the growth of melanoma and lung carcinoma in mouse models, and the depletion of ERK5 in keratocytes prevents tumorigenesis promoted by inflammation. Multiple reports have shown the potential therapeutic approach of both ERK5 knockdown and pharmacological kinase inhibition in regulating inflammation and tumorigenesis. Here we identify the role of ERK5 S496 phosphorylation, known to promote inflammatory signaling, as a novel mediator of exercise induced tumor microenvironment alterations. Utilizing two melanoma models, we found that aerobic exercise suppresses the growth of YUMMER 1.7 tumors but not B16F10 in mice. Consistent with this, single cell RNA sequencing revealed reductions in myeloid derived suppressor cells and a shift in T cell populations favoring a non-exhausted phenotype in YUMMER 1.7. Flow cytometry evaluation demonstrated significantly more CD8+ T cells in YUMMER 1.7, but not in B16F10, tumors from exercised mice. Interestingly, we found increased phosphorylation of ERK5 at the S496 residue when ECs were treated with serum from exercised mice ex vivo. We also found the crucial role of ERK5 S496 phosphorylation in promoting both inflammation and proliferation in ERK5 TEY motif phosphorylation (kinase activity) and transactivation-independent manner in both ECs and macrophages. We generated ERK5 S496A knock-in mice, and found that the ability of exercise to suppress YUMMER 1.7 tumor growth was completely lost in ERK5 S496A knock-in mice, suggesting that ERK5 S496 phosphorylation is a key in exercise-induced tumor growth suppression. We are currently evaluating immune cell infiltration into tumors with or without exercise in the ERK5 S496A knock-in model relative to wild type mice. Our data suggest that ERK5 S496 phosphorylation is a critical mediator of the tumor microenvironment. The often neglected role of ERK5 S496 signaling should be carefully considered in the interpretation of prior reports of ERK5 knockdown and pharmacological kinase inhibition relative to tumorigenesis.
Citation Format: Hannah Savage, Sumedha Pareek, Jonghae Lee, Riccardo Ballaro, Venkatasubrahman Samanthapudi, Kyung Ae Ko, Masaki Imanishi, Sivareddy Kotla, Jun-ichi Abe, Keri Schadler. Aerobic exercise suppresses melanoma tumor growth via upregulating ERK5 S496 phosphorylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 278.