Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.

Autor:	Rosano D; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; The Breast Cancer Now Toby Robins Research Center, The Institute of Cancer Research, London, United Kingdom., Sofyali E; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Dhiman H; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; The Breast Cancer Now Toby Robins Research Center, The Institute of Cancer Research, London, United Kingdom., Ghirardi C; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy., Ivanoiu D; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Heide T; Human Technopole, Milan, Italy.; Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom., Vingiani A; Istituto Nazionale Tumori, Milan, Italy., Bertolotti A; Istituto Nazionale Tumori, Milan, Italy., Pruneri G; Istituto Nazionale Tumori, Milan, Italy.; Department of Oncology and Haematology-Oncology, University of Milano, Milano, Italy., Canale E; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Dewhurst HF; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Saha D; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Slaven N; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley., Barozzi I; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; Centre for Cancer Research, Medical University of Vienna, Austria., Li T; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Zemlyanskiy G; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., Phillips H; Department of Surgery and Cancer, Imperial College London, London, United Kingdom., James C; Human Technopole, Milan, Italy.; Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom., Győrffy B; Department of Bioinformatics, Semmelweis University, Budapest, Hungary.; RCNS Cancer Biomarker Research Group, Budapest, Hungary.; Department of Biophysics, Medical School, University of Pecs, Pecs, Hungary., Lynn C; Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom., Cresswell GD; Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom., Rehman F; Charing Cross Hospital, Imperial College NHS Trust, London, United Kingdom., Noberini R; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy., Bonaldi T; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.; Department of Oncology and Haematology-Oncology, University of Milano, Milano, Italy., Sottoriva A; Human Technopole, Milan, Italy.; Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom., Magnani L; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.; The Breast Cancer Now Toby Robins Research Center, The Institute of Cancer Research, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 May 01; Vol. 14 (5), pp. 866-889.
DOI:	10.1158/2159-8290.CD-23-1161
Abstrakt:	Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs. Significance: This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. See related commentary by Llinas-Bertran et al., p. 704. This article is featured in Selected Articles from This Issue, p. 695. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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