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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234174 | GEO | 2024/04/16

REPOSITORIES: GEO

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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

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 epigenetic adaptation routes in dormant breast cancer cells [scRNA-Seq]

2024-04-16 | GSE234181 | GEO

Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

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.

2024-05-23 | PXD038030 | Pride

Comparative transcriptome of proliferative cells, dormant cells and awaken cells throught a DDR1 depletion

Project description:The goal of this study is to compare the trancriptome of proliferative THEP3 cells to their dormant counterpart DHEP3 and an awaken version through DDR1 receptor depletion (shRNA control verus shRNA DDR1) to identify target genes involved in the dormancy state and the awakening process from where metatsiss will arise.

2021-10-20 | GSE182890 | GEO

Identifying dormant cells in colorectal cancer spheroids

Project description:Cellular dormancy and heterogeneous cell cycle lengths provide important explanations for treatment failure following adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC) yet the molecular control of the dormant versus cycling state remains unknown. In CRCs dormant cells are found to be highly clonogenic and resistant to chemotherapies. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumour cells.

2018-05-21 | GSE114012 | GEO

Co-culture of human prostate cancer cells and mouse osteoblasts as a model for tumor dormancy in bone metastasis

Project description:Prostate cancer (PCa) cells, when disseminated to the bone, may stay quiescent or dormant for years before proliferation into overt metastases. Previous studies suggest that osteoblasts, the bone forming cells, may be responsible for induction of dormancy of bone-disseminated prostate cancer cells.

2023-10-23 | GSE210751 | GEO

RNAseq on PYMT cells treated with TGFB2 and/or BMP4 in 3D matrigel

Project description:Dormancy of disseminated tumor cells in secondary organs leads to late breast cancer-related deaths after relapse. The bone marrow is one of the primary breast cancer metastatic sites and is associated with poor prognosis. Here, we investigated the role of major factors of the bone marrow, BMP4 and TGF?2, in regulating cancer cell dormancy. Unexpectedly, we observed that TGF?2 and BMP4 have a synergistic effect that induces dormancy in both normal and transformed mammary stem cells. Several assays (3D matrigel, FUCCI Cell Cycle Indicator) showed that co-exposure to TGF?2 and BMP4 had a stronger anti-proliferative effect than each ligand alone. In addition, transformed cells fully retained this synergistic effect while they became less sensitive to individual cytokines. Surprisingly, single-cell RNAseq analysis revealed the heterogeneity of the G0 compartment at the transcriptomic level. We identified a unique deep dormant cluster under TGF?2 and BMP4 co-exposure characterized by a blended signature from treatments by TGF?2 or BMP4 alone. These findings reveal that disseminated breast cancer cells in the bone marrow are placed in a deep dormant stage by the synergistic effect of TGF?2 and BMP4 that neither factor can achieve alone. Lastly, our data suggest that the local BMP4 levels decrease with tissue aging and can therefore contribute to dormant cell awakening. By providing a better understanding of BMP4/TGF?2 signaling, our results open opportunities to prevent cancer relapse.

2024-05-10 | GSE232164 | GEO

Gene expression profiling of early primary breast cancer to identify prognostic markers and associated pathways

Project description:Retrospective series of primary breast cancer patients who received surgery between 1989 and 1992. Patients received adjuvant chemotherapy and/or adjuvant hormone therapy, or no adjuvant treatment. Tamoxifen was used as endocrine therapy for 5 years in ER+ BC patients. Patients who were <50 years of age, with lymph node positive tumors, or ER– and/or >3 cm in diameter, received adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for six cycles, in a thrice weekly intravenous regimen. Patients >50 years of age with ER–, lymph node–positive tumors also received CMF.

2011-07-08 | GSE22219 | GEO

microRNA expression profiling of early primary breast cancer to identify prognostic markers and associated pathways

2011-07-08 | GSE22216 | GEO

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