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Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx-mediated resistance to HER2-targeting therapies

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

Proceedings of the National Academy of Sciences - PNAS, 2024-05, Vol.121 (20), p.e2322688121-e2322688121 [Periódico revisado por pares]

United States: National Academy of Sciences

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Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx-mediated resistance to HER2-targeting therapies
Autor: 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
Assuntos: Animals ; Biological Sciences ; Brain ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Brain Neoplasms - secondary ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Communication ; Cell culture ; Cell interactions ; Cell Line, Tumor ; Chromatin ; Coculture Techniques ; Drug Resistance, Neoplasm ; Epidermal growth factor receptors ; ErbB Receptors - antagonists & inhibitors ; ErbB Receptors - metabolism ; ErbB-2 protein ; Female ; Gene expression ; Glycocalyx - metabolism ; Glycoproteins ; Humans ; Immunodeficiency ; Immunofluorescence ; Intracellular signalling ; Metastases ; Metastasis ; Mice ; Mucin ; Mucin-1 - genetics ; Mucin-1 - metabolism ; Mucinase ; Mucins ; Pharmacology ; Quinolines - pharmacology ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - metabolism ; Signal Transduction ; Stromal cells ; Stromal Cells - metabolism ; Stromal Cells - pathology ; Tumors
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2024-05, Vol.121 (20), p.e2322688121-e2322688121
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Contributed by Kornelia Polyak; received December 22, 2023; accepted March 27, 2024; reviewed by Susan L. Bellis and David Lyden
1M.-A.G. and L.E.S. contributed equally to this work.
Descrição: Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive 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 HER2-targeting 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 HER2-targeting therapies in breast cancer brain metastases.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx-mediated resistance to HER2-targeting therapies

United States: National Academy of Sciences

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