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

AI Article Synopsis

  • Brain metastatic breast cancer poses significant treatment challenges due to therapeutic resistance, particularly in patients with metastatic HER2-positive types.
  • Research indicates that interactions between breast cancer cells and surrounding stromal cells in 3D cultures contribute to this resistance, notably against the HER2-targeting drug neratinib.
  • The study found that increased production of mucins and bulky glycoproteins in cancer cells, which are linked to resistance mechanisms, was enhanced in brain metastases compared to primary tumors, suggesting potential targets for improving treatment efficacy.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11098130PMC
http://dx.doi.org/10.1073/pnas.2322688121DOI Listing

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