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

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

PROVIDER: PRJNA980235 | ENA |

REPOSITORIES: ENA

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

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

| PRJNA980234 | ENA

Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells

Project description:Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells

| PRJNA980241 | ENA

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

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

| PRJNA980249 | ENA

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

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

| PRJNA980226 | ENA

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

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

2024-04-16 | GSE234171 | GEO

Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-04-16 | GSE234185 | GEO

Coordinated excitatory and inhibitory circuits governing unpredictable threat induced anxiety

Project description:Anxiety is elicited by excessive apprehension about unpredictable threats. However, the neural circuit governing unpredictable threat induced anxiety remains unclear. Here, we found ventral bed nucleus of the stria terminalis (vBNST) GABAergic neurons displayed selective activation to unpredictable threats by means ofthrough coordinated excitatory input from insular cortex (IC) glutamergic neurons and inhibitory input from lateral nucleus of the amygdala (CeL) somatostatin (SOM) neurons. Using activity-dependent neuronal tagging technology, we found that unpredictable threat responsive cells in vBNST drive freezing and anxiety via projections to ventral lateral periaqueductal grey (vlPAG) and median nucleus of the amygdala (CeM) respectively. Finally, we identified KCNQ3 plays an essential role in hyperactivity of vBNST GABAergic neurons and induced anxiety. These data identified a forward inhibitory circuit that determine the selective activation of vBNST in unpredictable threat and anxiety, and suggest that Kcnq3 KCNQ3 channel acts as a promising target in treatment of anxiety disorder following unpredictable stress.

2024-02-19 | GSE255670 | GEO

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