Abstract 72: Ablation of WNT10B alters the tumor microenvironment in highly metastatic breast cancer, altering paclitaxel response
Authors: Kelso Hannah R. , Perkins Rachel S. , Ayachi Ikbale El , Alva-Ornelas Jackelyn A. , Seagroves Tiffany N. , Seewaldt Victoria L. , Krum Susan A. , Miranda-Carboni Gustavo Adolfo 
Published: April 2023

Triple-negative breast cancer (TNBC) has the worst survival outcome and the greatest incidence of metastasis among breast cancer subtypes. We have shown that the WNT10B network, composed of β-CATENIN, HMGA2, and EZH2, is predictive of higher rates of TNBC metastasis and poorer overall survival in TNBC. The stroma-tumor microenvironment (TME) interactions in metastatic breast cancer remain poorly defined, and prior to our work, the role of WNT10B signaling in the TME was unknown. Global gene expression profiling of the Wnt10bKO total mammary glands demonstrated a gene signature consistent with altered metabolism and markers promoting adipocyte differentiation. Wnt10b ablation in the mammary gland increases adipogenic differentiation and decreases the number of mammary gland terminal-end buds, and epithelia to stroma/fibroblast cell ratios. Therefore, we questioned the role of WNT10B in stromal cancer-associated fibroblast (CAFs) and cancer-associated adipocytes (CAAs) in the TME of transformed mammary glands. By backcrossing our Wnt10bKO mice to the highly metastatic MMTV-PyMT (PyMT) transgenic mammary tumor model, we demonstrated alteration in the age of tumor onset, changes in the incidence of transformation of thoracic and abdominal-inguinal tumors, and impacts on survival rates. Moreover, adipogenic markers are higher and persist through transformation in PyMTWnt10bKO mice compared to PyMT mice. Proliferation, migration, and invasion are also impacted in the PyMTWnt10bKO CAFs when co-cultured with PyMT tumor cells. The ability of PyMTWnt10bKO CAFs to alter cellular plasticity and generate CAAs is higher than PyMT CAFs. Additionally, PyMTWnt10bKO CAFs lose expression of canonical Wnt markers DVL and LRP and gain non-canonical Wnt signaling via WNT5B/ROR pathways that persist in the KO CAAs. We also observed alterations in chemoresistance in KO tumor epithelium. The resistance to paclitaxel from enriched PyMT epithelia from thoracic tumors was higher than epithelia enriched from the abdominal-inguinal tumors. Interestingly, the Wnt10bKO TME inverted the response to paclitaxel and the abdominal-inguinal epithelial tumor cells were more resistant than those from the thoracic epithelium. Furthermore, resistance to paclitaxel was associated with higher responses to PRI-724, a CBP-β-CATENIN inhibitor. Neither WT nor KO epithelial subtypes were resistant to olaparib exposure. Therefore, we conclude that Wnt10b is essential to educate highly metastatic breast cancer stromal cells to promote growth, metastatic colonization, and resistance to paclitaxel.

Citation Format: Hannah R. Kelso, Rachel S. Perkins, Ikbale El Ayachi, Jackelyn A. Alva-Ornelas, Tiffany N. Seagroves, Victoria L. Seewaldt, Susan A. Krum, Gustavo Adolfo Miranda-Carboni. Ablation of WNT10B alters the tumor microenvironment in highly metastatic breast cancer, altering paclitaxel response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 72.