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Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

ABSTRACT: Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

PROVIDER: PRJNA506208 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8210370_1.fastq.gz	Fastqsanger.gz
	SRR8210370_2.fastq.gz	Fastqsanger.gz
	SRR8210380_1.fastq.gz	Fastqsanger.gz
	SRR8210380_2.fastq.gz	Fastqsanger.gz
	SRR8210371_1.fastq.gz	Fastqsanger.gz

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Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

Project description:Resistant tumours are thought to arise from the action of Darwinian selection on intratumoral genetic heterogeneity. However, clonal selection is incompatible with the late recurrence often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. In the present study, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub-population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. PA cells show reduced oestrogen receptor α activity but increased features of quiescence and migration. We find evidence for sub-clonal expression of this PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

2019-07-17 | GSE122743 | GEO

Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy.

Project description:Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

| S-EPMC6718416 | biostudies-literature

Phosphoproteomics measurement of clonal endocrine therapy sensitive and resistant breast cancer populations

Project description:Around two thirds of breast tumors are characterized by the expression of estrogen receptor α and are therapeutically treated by blocking estrogen signaling. First line endocrine therapeutics are Tamoxifen which displaces estrogen form its receptor preventing receptor activation and aromatase inhibitors which prevent the formation of estrogen and thereby hormone-deprive the tumors. Therapy resistance remains a major clinical problem, especially for patients with late-stage diagnoses. Tumor heterogeneity may promote therapy resistance either through the selection of pre-existing rare clones or by providing a repertoire of cells that may develop resistance over time. In order to study endocrine therapy resistance on a clonal level, we have developed barcoded (allowing the tracking of single cells) endocrine therapy sensitive and resistant breast cancer cell lines. From these complex cell pools, multiple single cells characterized by a specific barcode were isolated and grown out. We then subjected the clones to phosphoproteomics measurement by Mass spectrometry. Based on their phosphorylation pattern, the kinase activity profiles of endocrine therapy resistant clones were determined to identify differentially activated kinases with implications in therapy resistance.

2024-01-26 | PXD040478 | Pride

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.

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Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Project description:Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

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Targeting metabolic adaptations in the breast cancer–liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

Project description:Targeting metabolic adaptations in the breast cancer–liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

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Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

2013-05-01 | GSE37323 | GEO

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RNA sequencing of endocrine resistant breast cancer

Project description:*** This submission includes RNA data, with DNA files available under a different accession number*** Purpose: Endocrine therapy resistance remains the greatest challenge for treating hormone receptor positive breast cancer patients. We aim to identify molecular mechanisms underlying endocrine therapy resistance through in-depth genomic analysis of patient samples. Experimental Design: We collected tumors from 35 estrogen receptor positive breast cancer patients receiving endocrine therapy, of which 3 patients had intrinsic resistance and 19 patients developed acquired resistance. For each patient, multiple tumor specimens were collected during the course of treatment. We performed DNA whole exome sequencing and RNA sequencing on all tumor samples. DNA mutations, copy number alterations and RNA gene expression data were analyzed through supervised analyses comparing paired sensitive and resistant tumor samples to identify molecular features related to endocrine therapy resistance. Results: We identified mutations enriched in resistant tumors including ESR1 and GATA3. ESR1 D538G variant confers endocrine therapy resistance while E380Q variant confers hypersensitivity. We demonstrate that resistant tumors had distinct gene expression profiles and elevated signaling pathways including ER, HER2, GATA3, AKT, RAS and p63 signaling. Integrated analysis for individual patient highlighted the heterogeneity of endocrine therapy resistance mechanisms. Conclusions: Our results suggest that mechanisms underlying endocrine therapy resistance are highly heterogeneous with diverse changes in genomic and transcriptomic levels.

2022-09-01 | E-MTAB-9917 | biostudies-arrayexpress

MLL3 is a de novo Cause of Endocrine Therapy Resistance

Project description:MLL3 is a de novo Cause of Endocrine Therapy Resistance

| PRJNA685435 | ENA