PEAK1 Function in Breast Cancer Stroma

The cellular and molecular heterogeneity of solid tumors presents a significant hurdle in the effort to develop effective anti-cancer therapies. Since PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is a cytoskeleton-associated kinase that regulates growth factor receptor-integrin crosstalk to promote cell state plasticity and mesenchymal cell phenotypes, we hypothesized that PEAK1 expression in the mesenchymal compartment of the breast cancer (BC) microenvironment may contribute to tumor progression and/or therapy resistance. We report that elevated stromal expression of PEAK1 predicts breast cancer recurrence and that the correlation between PEAK1 and mesenchymal marker levels increases in the stroma of patients with relapsed disease. In agreement with these data, PEAK1 is expressed in patient-derived breast cancer-associated fibroblasts (CAFs) and other mesenchymal stroma cell (MSC) types. Co-xenografting CAFs or MSCs with HER2-positive and ER-positive breast cancer cells increased primary tumor mass and promoted targeted therapy resistance. Notably, PEAK1 knockdown in MSCs abrogated these in vivo pro-tumorigenic microenvironment phenotypes. To determine whether these PEAK1-dependent pro-tumorigenic effects of CAFs and MSCs are mediated by paracrine or juxtacrine mechanisms, breast cancer cells were grown in CAF/MSC conditioned media (CM) or co-culture conditions. Both CAF/MSC CM and co-culture conditions increased breast cancer cell proliferation/survival and resistance to HER2-targeted therapies, and MSC expression of PEAK1 was necessary for both CM- and co-culture-mediated breast cancer cell survival and therapy resistant phenotypes. Analysis of the MSC proteome revealed that PEAK1 sustains expression and BC secretome induced secretion of Cripto (TDGF1). Finally, elevated PEAK1/Cryptic levels predict poor breast cancer patient outcome. Taken together, this work identifies new PEAK1-dependent tumor microenvironment signaling vulnerabilities that may be harnessed to improve patient responses to current therapeutic interventions.