Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.
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Authors
Rosano, D
Sofyali, E
Dhiman, H
Ghirardi, C
Ivanoiu, D
Heide, T
Vingiani, A
Bertolotti, A
Pruneri, G
Canale, E
Dewhurst, HF
Saha, D
Slaven, N
Barozzi, I
Li, T
Zemlyanskiy, G
Phillips, H
James, C
Győrffy, B
Lynn, C
Cresswell, GD
Rehman, F
Noberini, R
Bonaldi, T
Sottoriva, A
Magnani, L
Sofyali, E
Dhiman, H
Ghirardi, C
Ivanoiu, D
Heide, T
Vingiani, A
Bertolotti, A
Pruneri, G
Canale, E
Dewhurst, HF
Saha, D
Slaven, N
Barozzi, I
Li, T
Zemlyanskiy, G
Phillips, H
James, C
Győrffy, B
Lynn, C
Cresswell, GD
Rehman, F
Noberini, R
Bonaldi, T
Sottoriva, A
Magnani, L
Document Type
Journal Article
Date
2024-05-01
Date Accepted
2024-02-20
Abstract
UNLABELLED: 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.
Citation
Cancer Discovery, 2024, 14 (5), pp. 866 - 889
Source Title
Cancer Discovery
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
2159-8290
2159-8290
Collections
Research Team
Evol Genomics & Modelling
Chromatin Biology
Breast Epige Plast & Evol
Chromatin Biology
Breast Epige Plast & Evol