| Literature DB >> 33878299 |
Igor L Bado1, Weijie Zhang1, Jingyuan Hu2, Zhan Xu1, Hai Wang1, Poonam Sarkar3, Lucian Li4, Ying-Wooi Wan5, Jun Liu1, William Wu6, Hin Ching Lo1, Ik Sun Kim1, Swarnima Singh7, Mahnaz Janghorban7, Aaron M Muscarella1, Amit Goldstein1, Purba Singh1, Hyun-Hwan Jeong8, Chaozhong Liu4, Rachel Schiff9, Shixia Huang10, Matthew J Ellis1, M Waleed Gaber3, Zbigniew Gugala11, Zhandong Liu12, Xiang H-F Zhang13.
Abstract
Estrogen receptor-positive (ER+) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.Entities:
Keywords: FGFR/EZH2 axis; barcoding; bone metastasis; bone tropism; chromatin alteration; clonal evolution; endocrine resistance; epigenomic reprogramming; osteogenic cells; stemness
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Year: 2021 PMID： 33878299 PMCID： PMC8062036 DOI： 10.1016/j.devcel.2021.03.008
Source DB: PubMed Journal: Dev Cell ISSN： 1534-5807 Impact factor: 12.270