Abstract 2140: Mesenchymal stromal cells expressing a PEAK1/Cripto axis sustain pro-survival NF-κB signaling in adjacent tumor cells to promote disease progression and therapy resistance
Authors: Sarkis Hamalian, Robert Güth, Ioannis Zervantonakis, Erika Duell, Jia-Ren Lin, Preston Shisgal, Justin Molnar, Cameron Geller, Megan Agajanian, Julia Tchou, Peter K. Sorger, Joan S. Brugge, Jonathan A. Kelber
Journal: Cancer Research (2018)

Abstract The cellular and molecular heterogeneity of solid tumors, like breast cancer, is a significant hurdle in the effort to develop effective therapies. The complex breast cancer microenvironment (BCME) includes mesenchymal stromal cells (MSCs) that engage in paracrine/juxtacrine signaling with adjacent tumor cells to support disease progression. Since PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is a cytoskeleton-associated kinase that regulates growth factor-integrin signaling crosstalk in mesenchymal cell types and recent evidence demonstrates that stromal expression of PEAK1 correlates with breast cancer recurrence, we hypothesized that PEAK1 expression in the mesenchymal compartment of the BCME promotes tumorigenesis. We report that PEAK1 is expressed in patient-derived cancer-associated fibroblasts (CAFs) from all breast cancer subtypes. Additionally, PEAK1hi CAF conditioned media promoted breast cancer cell (BCC) proliferation, migration and therapy resistance in vitro. We established in vitro co-culture and in vivo co-xenografting models for evaluating the effects of defined MSC populations on BCC proliferation/survival, metastasis and therapy response. Co-xenografting PEAK1hi CAFs or MSCs with BCCs increased the mass of HER2-positive and ER-positive primary tumors. In agreement with these data, co-culturing MSCs with BCCs promoted cancer cell proliferation and resistance to lapatinib or tamoxifen treatment, while MSC conditioned media supported BCC expansion under serum-free conditions in vitro. Notably, PEAK1 knockdown in MSCs abrogated their ability to promote tumor growth in vivo and therapy/stress resistance in vitro. Using the highly multiplexed cyclic immunofluorescence (CycIF) platform, we analyzed tumor cell states in these MSC-BCC co-cultures at different time points following lapatinib treatment. We demonstrate that MSCs sustain NF-κB (p65) signaling and anti-apoptotic gene expression within BCCs in the presence of lapatinib. Finally, we discovered that PEAK1 is required for MSC expression of Cripto, a GPI-anchored glycoprotein previously reported to activate NF-κB signaling in trans. Taken together, this work identifies new PEAK1-dependent stroma-tumor signaling vulnerabilities that may be exploited for improving patient responses to current therapeutic interventions. Citation Format: Sarkis Hamalian, Robert Güth, Ioannis Zervantonakis, Erika Duell, Jia-Ren Lin, Preston Shisgal, Justin Molnar, Cameron Geller, Megan Agajanian, Julia Tchou, Peter K. Sorger, Joan S. Brugge, Jonathan A. Kelber. Mesenchymal stromal cells expressing a PEAK1/Cripto axis sustain pro-survival NF-κB signaling in adjacent tumor cells to promote disease progression and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2140.