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Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells [RNA-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: GSE234171 | GEO | 2024/04/16

REPOSITORIES: GEO

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Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells [scRNA-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 | GSE234181 | 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

Modeling androgen deprivation therapy-induced prostate cancer dormancy and its clinical implications

Project description:Purpose: Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer (PCa) treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced PCa dormancy remains poorly understood due to the challenge in acquiring clinical dormant PCa cells and the lack of representative models. We, therefore, aimed to develop clinically relevant models that can be used for studying ADT-induced PCa dormancy. Experimental design: Dormant PCa models were established by castrating mice bearing PCa patient-derived xenografts (PDXs) of hormonal naïve or sensitive PCa. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and post-castration (dormant) PDX tissues were subjected to morphological and transcriptome profiling analyses. Results: We established eleven ADT-induced dormant PCa models that closely mimicked the clinical courses of ADT-treated PCa. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in pre-castration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve PCa and clinical outcome in castration-resistant PCa treated with ADT or androgen-receptor pathway inhibitors.

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

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

Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

Project description:Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and re-populate the tumor. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and re-activation. In this study we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state which is switched ‘on’ by engagement with bone lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodeling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy targeting dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.

2015-11-30 | GSE57695 | GEO

mRNA oxidation data from dry dormant and after-ripened wheat seeds

Project description:After-ripening induced seed dormancy release in wheat is associated with mRNA oxidation. We used Affymetrix GeneChip Wheat Genome Array to identify mRNAs differentially oxidized by after-ripening Dormant and after-ripened seeds in dry state were used for isolating oxidized mRNAs and hybridization on Affymetrix GeneChip. After-ripened seeds were generated by storing dormant seeds at room temperature for 10 months.

2013-12-15 | E-GEOD-41949 | biostudies-arrayexpress

affy_tour_2012-02-Study of sunflower seed dormancy by translatome analysis

Project description:affy_tour_2012-02 - Identification of transcripts that are addressed to traduction in imbibed seeds in relation with dormancy: comparison of the translatome in Dormant versus Non-Dormant seeds -- At harvest seeds are dormant. They stay dormant if they are stored at -20°C (D) and become non-dormant (ND) if they are stored 2 months at +20°C. Polysomal fractions were purified on sucrose gradients from sunflower axis isolated from dormant and non-dormant seeds imbibed at 10°C during 3h, 15h or 24h. - These fractions allow to identify the transcripts addressed to translation (translatome) during the seed imbibition process (3, 15 and 24h) - The translatome of 2 types of seeds are compared: Dormant vs Non-Dormant at the 3 time points. 18 arrays - SUNFLOWER; time course,treated vs untreated comparison

2013-10-30 | E-GEOD-41944 | biostudies-arrayexpress

Single Cell Analysis Unveils the Role of the Tumor Immune Microenvironment and Notch Signaling in Dormant Minimal Residual Disease

Project description:Understanding the complex ecosystem that promotes dormant cell survival and elucidating those factors that eventually overcome growth constraints and result in proliferation may provide new insights and help identify novel strategies to prolong dormancy and prevent recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of tumor dormancy, we utilized a novel immunocompetent transgenic model to study residual disease, dormancy, and relapse. We discovered a significant reorganization of cancer cell structures, stroma, and immune cells with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. Additionally, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis including stem cell development, epithelial-mesenchymal transition, and immune cell homeostasis during dormancy. An anti-Jagged-1 inhibitory antibody prolonged dormancy and delayed tumor recurrence due to the pleotropic effects of inhibiting the Jagged-1/Notch signaling pathway both in the tumor cells and the microenvironment.

2021-12-18 | GSE171464 | GEO

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