Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx- mediated resistance to HER2targeting therapies

• 成果类型: Article
• 署名作者: Goyette, Marie-Anne; Stevens, Laura E.; Depinho, Carolyn R.; Seehawer, Marco; Nishida, Jun; Li, Zheqi; Wilde, Callahan M.; Li, Rong; Qiu, Xintao; Pyke, Alanna L.; Zhao, Stephanie; Lim, Klothilda; Tender, Gabrielle S.; Northey, Jason J.; Riley, Nicholas M.; Long, Henry W.; Bertozzi, Carolyn R.; Weaver, Valerie M.; Polyak, Kornelia
• 署名单位: Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Stanford University; University of California System; University of California San Francisco; Howard Hughes Medical Institute; Stanford University; Stanford University; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10469
• DOI: 10.1073/pnas.2322688121
• 发表日期: 2024-05-14
• 关键词: tumor microenvironment; survival; fibroblasts; package; mucins

摘要

Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer - associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top - up - regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma - contact and no - contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx - induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2targeting therapies in breast cancer brain metastases.