Simultaneous isolation of hormone receptor-positive breast cancer organoids and fibroblasts reveals stroma-mediated resistance mechanisms
AuthorsHogstrom, Jenny M
Cruz, Kayla A
Selfors, Laura M
Ward, Madelyn N
Mehta, Tejas S
Collins, Laura C
Patel, Jaymin M
UMass Chan AffiliationsRadiology
Document TypeJournal Article
hormone receptor–positive breast cancer
luminal breast cancer
tumor-stroma cross talk
MetadataShow full item record
AbstractRecurrent hormone receptor-positive (HR+) breast cancer kills more than 600,000 women annually. Although HR+ breast cancers typically respond well to therapies, approximately 30% of patients relapse. At this stage, the tumors are usually metastatic and incurable. Resistance to therapy, particularly endocrine therapy is typically thought to be tumor intrinsic (e.g., estrogen receptor mutations). However, tumor-extrinsic factors also contribute to resistance. For example, stromal cells, such as cancer-associated fibroblasts (CAFs), residing in the tumor microenvironment, are known to stimulate resistance and disease recurrence. Recurrence in HR+ disease has been difficult to study due to the prolonged clinical course, complex nature of resistance, and lack of appropriate model systems. Existing HR+ models are limited to HR+ cell lines, a few HR+ organoid models, and xenograft models that all lack components of the human stroma. Therefore, there is an urgent need for more clinically relevant models to study the complex nature of recurrent HR+ breast cancer, and the factors contributing to treatment relapse. Here, we present an optimized protocol that allows a high take-rate, and simultaneous propagation of patient-derived organoids (PDOs) and matching CAFs, from primary and metastatic HR+ breast cancers. Our protocol allows for long-term culturing of HR+ PDOs that retain estrogen receptor expression and show responsiveness to hormone therapy. We further show the functional utility of this system by identifying CAF-secreted cytokines, such as growth-regulated oncogene α , as stroma-derived resistance drivers to endocrine therapy in HR+ PDOs.
SourceHogstrom JM, Cruz KA, Selfors LM, Ward MN, Mehta TS, Kanarek N, Philips J, Dialani V, Wulf G, Collins LC, Patel JM, Muranen T. Simultaneous isolation of hormone receptor-positive breast cancer organoids and fibroblasts reveals stroma-mediated resistance mechanisms. J Biol Chem. 2023 Jul 7;299(8):105021. doi: 10.1016/j.jbc.2023.105021. Epub ahead of print. PMID: 37423299; PMCID: PMC10415704.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/52444
NotesTejas S. Mehta is an Associate Professor in the Department of Radiology at UMass Chan Medical School.
Rights© 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).; Attribution 4.0 International
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Except where otherwise noted, this item's license is described as © 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).