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Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells [scRNA-Seq]

ABSTRACT: Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ETs). Adjuvant ETs delay relapse by targeting clinically undetectable micro-metastatic deposits, yet up to 50% of patients receiving ET relapse at a constant rate over the course of decades after surgery. The mechanisms driving these clinical dynamics are largely unknown but likely involve dormancy. We developed two approaches to study the fate of dormant cells in long-term experiments. Firstly, we profiled samples from late relapse (10-35 yrs.) and patients treated with 16-44 months of neoadjuvant ETs until progression to dissect the contribution of genetic and transcriptional changes to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual lineages in unperturbed parallel experiments through several months. Collectively our data demonstrate that ETs induce a heritable cell state transition into dormancy via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably via epigenetic erosion. 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 with profound implications for breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234181 | GEO | 2024/04/16

REPOSITORIES: GEO

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Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells [RNA-Seq]

Project description:Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ETs). Adjuvant ETs delay relapse by targeting clinically undetectable micro-metastatic deposits, yet up to 50% of patients receiving ET relapse at a constant rate over the course of decades after surgery. The mechanisms driving these clinical dynamics are largely unknown but likely involve dormancy. We developed two approaches to study the fate of dormant cells in long-term experiments. Firstly, we profiled samples from late relapse (10-35 yrs.) and patients treated with 16-44 months of neoadjuvant ETs until progression to dissect the contribution of genetic and transcriptional changes to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual lineages in unperturbed parallel experiments through several months. Collectively our data demonstrate that ETs induce a heritable cell state transition into dormancy via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably via epigenetic erosion. 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 with profound implications for breast cancer.

2024-04-16 | GSE234171 | GEO

Long-term multi-modal recording reveals unpredictable nongenetic adaptation routes in dormant breast cancer cells. [gBarcodes]

Project description:Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ET). Adjuvant treatment delays relapse by targeting hidden micro-metastatic deposits, yet up to 50% of treated patients experience recurrent disease, often many years after surgery. The mechanisms driving these subtype-specific clinical dynamics are largely unknown but likely involve dormancy2. We developed two approaches to study the long-term fate of dormant cells in unprecedented details. Firstly, we took advantage of a rare cohort of patients treated upfront with first line ETs until progression to dissect the contribution of genomic events to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual clonal lineages in parallel unperturbed systems during a period of several months. Collectively our data suggest that ETs induce an inherently unstable persister dormant state in a stochastically selected fraction of lineages. Over time, single cells spontaneously escape dormancy and divergently adapt via heritable transcriptional reprogramming, often developing distinct collateral resistance. Overall, this study uncovers previously unsuspected roles for non-genetic plasticity during dormancy with profound clinical implications for breast cancer.

2024-04-16 | GSE234174 | GEO

Long-term multi-modal recording reveals unpredictable nongenetic adaptation routes in dormant breast cancer cells. [WGS]

Project description:Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ET). Adjuvant treatment delays relapse1,2 by targeting hidden micro-metastatic deposits, yet up to 50% of treated patients experience recurrent disease, often many years after surgery1. The mechanisms driving these subtype-specific clinical dynamics are largely unknown but likely involve dormancy2. We developed two approaches to study the long-term fate of dormant cells in unprecedented details. Firstly, we took advantage of a rare cohort of patients treated upfront with first line ETs until progression to dissect the contribution of genomic events to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual clonal lineages in parallel unperturbed systems during a period of several months. Collectively our data suggest that ETs induce an inherently unstable persister dormant state in a stochastically selected fraction of lineages. Over time, single cells spontaneously escape dormancy, often without developing resistance. Ultimately, single lineages and divergently divergently adapt via heritable transcriptional reprogramming, often developing distinct collateral resistance. Overall, this study uncovers previously unsuspected roles for non-genetic plasticity during dormancy with profound clinical implications for breast cancer.

2024-04-16 | GSE234173 | GEO

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Project description:Hormone dependent breast cancer (HDBC) is the most commonly diagnosed tumor type in women. Adjuvant endocrine therapies (ET) have been the cornerstone in the clinical management of HDBC patients for over forty years. A vast proportion of HDBC patients incur long periods of clinical dormancy following ET, with tumour awakening appearing at a steady pace for up to 25 years (Pan et al., 2017). Extensive genomic studies have demonstrated that 15-30% of clinical relapses develop recurrent genomic changes which contribute to drug resistance (i.e. ESR1 activating mutations) (Bertucci et al., 2019; Magnani et al., 2017; Razavi et al., 2018). However, even in these cases, there is no conclusive evidence around the pre-existence vs. de novo nature of these events. Here, we analyzed histone PTMs in dormant and awakened breast cancer cells treated with endocrine therapy.

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2022-01-11 | GSE193500 | GEO

RNA-sequencing of D2A1 and D2.OR cell lines in both 2D and 3D cultures

Project description:Reactivation of dormant cancer cells can lead to cancer relapse, metastasis and patient death. Dormancy is a non-proliferative state and is linked to late relapse and death. No targeted therapy is currently available to eliminate dormant cells, highlighting the need for a deeper understanding and reliable models. Here, we thoroughly characterize the dormant D2.OR and proliferative D2A1 breast cancer cell line models in vivo and in vitro, and assess if there is overlap between a dormant and a senescent phenotype. We show that D2.OR but not D2A1 cells become dormant in the liver of an immunocompetent model. In vitro, we show that D2.OR cells are polyploid ER+/Her2+ cells, and in response to a 3D environment are growth arrested in G1, of which a subpopulation resides in a 4NG1 state. The dormancy state is reversible, and not associated with a senescence phenotype. This will aid future research on breast cancer dormancy.

2021-09-19 | GSE172882 | GEO

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Project description:Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Massive parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies triggers the emergence of transient features which could ultimately be exploited to hinder the adaptive process.

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Project description:Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERKlow:P-p38high dormancy signaling ratio, along with Ki67− expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domain 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 down-regulation. Thus, our biomaterial-based approach will enable systematic screens for previously unidentified compounds suited to eradicate potentially relapsing dormant cancer cells.

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