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

Rosano, Dalia; Sofyali, Emre; Dhiman, Heena; Ghirardi, Chiara; Ivanoiu, Diana; Heide, Timon; Vingiani, Andrea; Bertolotti, Alessia; Pruneri, Giancarlo; Canale, Eleonora; Dewhurst, Hannah F.; Saha, Debjani; Slaven, Neil; Barozzi, Iros; Li, Tong; Zemlyanskiy, Grigory; Phillips, Henry; James, Chela; Győrffy, Balázs; Lynn, Claire; Cresswell, George D.; Rehman, Farah; Noberini, Roberta; Bonaldi, Tiziana; Sottoriva, Andrea; Magnani, Luca

doi:10.1158/2159-8290.cd-23-1161

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

Journal Article · 25 March 2024 · Cancer Discovery

DOI: https://doi.org/10.1158/2159-8290.cd-23-1161 · OSTI ID:2470909

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Imperial College, London (United Kingdom); Institute of Cancer Research (ICR), London (United Kingdom)
Imperial College, London (United Kingdom)
European Institute of Oncology (IEO), Milano (Italy)
Human Technopole, Milan (Italy); Institute of Cancer Research (ICR), London (United Kingdom)
Istituto Nazionale dei Tumori (INT), Milano (Italy); Univ. di Milano (Italy)
Istituto Nazionale dei Tumori (INT), Milano (Italy)
Istituto Nazionale dei Tumori (INT), Milano (Italy); University of Milano (Italy)
Imperial College, London (United Kingdom); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Imperial College, London (United Kingdom); Medical University of Vienna (Austria)
Semmelweis University, Budapest (Hungary); RCNS Cancer Biomarker Research Group, Budapest (Hungary); University of Pecs (Hungary)
Institute of Cancer Research (ICR), London (United Kingdom)
Imperial College NHS Trust, London (United Kingdom). Charing Cross Hospital
European Institute of Oncology (IEO), Milano (Italy); University of Milano (Italy)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: Cancer Research UK (CRUK); USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470909

Journal Information:: Cancer Discovery, Journal Name: Cancer Discovery Journal Issue: 5 Vol. 14; ISSN 2159-8274

Publisher:: American Association for Cancer ResearchCopyright Statement

Country of Publication:: United States

Language:: English

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

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