American Association for Cancer Research
Browse
cd-23-1161_supplementary_figure_s6_suppsf6.pdf (78.16 kB)

Supplementary Figure S6 from Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells

Download (78.16 kB)
journal contribution
posted on 2024-05-01, 07:42 authored by Dalia Rosano, Emre Sofyali, Heena Dhiman, Chiara Ghirardi, Diana Ivanoiu, Timon Heide, Andrea Vingiani, Alessia Bertolotti, Giancarlo Pruneri, Eleonora Canale, Hannah F. Dewhurst, Debjani Saha, Neil Slaven, Iros Barozzi, Tong Li, Grigory Zemlyanskiy, Henry Phillips, Chela James, Balázs Győrffy, Claire Lynn, George D. Cresswell, Farah Rehman, Roberta Noberini, Tiziana Bonaldi, Andrea Sottoriva, Luca Magnani

Spatially resolved changes in the transcriptional profile of tumour-associated immune cells and stroma (Patient 1-3, rare cohort treated with long-term ET until progression)

Funding

Cancer Research UK (CRUK)

Horizon 2020 Framework Programme (H2020)

History

ARTICLE ABSTRACT

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. 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