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Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence

ABSTRACT: Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence

PROVIDER: PRJNA807901 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18056672_1.fastq.gz	Fastqsanger.gz
	SRR18056672_2.fastq.gz	Fastqsanger.gz
	SRR18056673_1.fastq.gz	Fastqsanger.gz
	SRR18056673_2.fastq.gz	Fastqsanger.gz

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Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence

Project description:Estrogen receptor α-positive (ER+) breast cancers (BCs) represent more than 70% of all breast cancers and pose a particular clinical challenge because they recur up to decades after initial diagnosis and treatment. The mechanisms governing tumor cell dormancy and latent disease remain elusive due to a lack of adequate models. Here, we compare tumor progression of ER+ and triple-negative (TN) BC subtypes with a clinically relevant mouse intraductal xenografting approach (MIND). Both ER+ and TN BC cells disseminate already during the in situ stage. However, TN disseminated tumor cells (DTCs) proliferate at the same rate as cells at the primary site and give rise to macro-metastases. ER+ DTCs have low proliferative indices, form only micro-metastases and lose epithelial characteristics. Single cell RNA sequencing reveals that dormant DTCs harbor different Epithelial-Mesenchymal Plasticity (EMP)-states, reflective of their heterogeneous and plastic nature. Dormant DTCs are in a mesenchymal-like state, with decreased CDH1 and increased ZEB2 and VIM expression levels, as well as matrisome-related genes, like FN1, ELN, COL3A1, and others. On the other hand, proliferative DTCs are epithelial-like, and express CDH1, EPCAM, KRT18, and ESR1. EMP is very rare in primary tumour cells and is not required for invasion or metastasis. In vivo, forced transition to the epithelial state through ectopic E-cadherin expression overcomes dormancy with increased growth of lung metastases. We conclude that EMP is essential for the generation of a dormant cell state and the development of latent disease. Targeting exit from EMP is of therapeutic potential.

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Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence.

Project description:More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER+). A clinical challenge of ER+ BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER+ and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER+ BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER+ BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential.

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Project description:Cell dormancy is a major factor leading to drug resistance as well as the high rate of late recurrence and mortality in estrogen receptor-positive (ER+) breast cancer. Although some studies have highlighted the significant impact of the microenvironment on dormant cells, they have largely overlooked the mechanical forces stemming from the stiffness of the surrounding extracellular matrix. Previously, we demonstrated that soft matrix promotes tumor cell proliferation and migration, while stiff matrix induces tumor cell dormancy and drug resistance. In this study, we present a comprehensive analysis of the proteome and phosphoproteome in response to gradient changes in matrix stiffness, elucidating the mechanisms behind cell dormancy induced drug resistance. Overall, we found that membrane transport and anti-apoptotic processes may be mainly involved in mechanical force induced dormancy resistance of ER+ breast cancer cells.

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