Phenotypic heterogeneity driven by plasticity of the intermediate EMT state governs disease progression and metastasis in breast cancer

Brown, MS and Abdollahi, B and Wilkins, OM and Lu, H and Chakraborty, P and Ognjenovic, NB and Muller, KE and Jolly, MK and Christensen, BC and Hassanpour, S and Pattabiraman, DR (2022) Phenotypic heterogeneity driven by plasticity of the intermediate EMT state governs disease progression and metastasis in breast cancer. In: Science Advances, 8 (31).

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Abstract

The epithelial-to-mesenchymal transition (EMT) is frequently co-opted by cancer cells to enhance migratory and invasive cell traits. It is a key contributor to heterogeneity, chemoresistance, and metastasis in many carcinoma types, where the intermediate EMT state plays a critical tumor-initiating role. We isolate multiple distinct single-cell clones from the SUM149PT human breast cell line spanning the EMT spectrum having diverse migratory, tumor-initiating, and metastatic qualities, including three unique intermediates. Using a multiomics approach, we identify CBFβ as a key regulator of metastatic ability in the intermediate state. To quantify epithelial-mesenchymal heterogeneity within tumors, we develop an advanced multiplexed immunostaining approach using SUM149- derived orthotopic tumors and find that the EMT state and epithelial-mesenchymal heterogeneity are predictive of overall survival in a cohort of stage III breast cancer. Our model reveals previously unidentified insights into the complex EMT spectrum and its regulatory networks, as well as the contributions of epithelial-mesenchymal plasticity (EMP) in tumor heterogeneity in breast cancer.

Item Type:	Journal Article
Publication:	Science Advances
Publisher:	American Association for the Advancement of Science
Additional Information:	The copyright for this article belongs to the American Association for the Advancement of Science.
Keywords:	Cancer cells; Cell culture; Clone cells; Diseases; Pathology, Breast Cancer; Cancer cells; Cell clones; Chemoresistance; Disease progression; Epithelial to Mesenchymal transitions; Human breast; Single cells; Transition spectrum; Transition state, Tumors, breast tumor; disease exacerbation; epithelial mesenchymal transition; female; genetics; human; metastasis; pathology; tumor cell line, Breast Neoplasms; Cell Line, Tumor; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Neoplasm Metastasis
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	30 Aug 2022 05:41
Last Modified:	30 Aug 2022 05:41
URI:	https://eprints.iisc.ac.in/id/eprint/76270

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