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Phenotypic heterogeneity driven by plasticity of the intermediate EMT state governs disease progression and metastasis in breast cancer [RNA-seq]

ABSTRACT: The Epithelial-to-Mesenchymal Transition (EMT) is a dynamic cellular program that is frequently used by cancer cells to increase migratory and invasive cell characteristics. It is a key contributor to both heterogeneity and chemo-resistance and metastasis in many solid tumors, including triple negative breast cancer. In particular, the intermediate or hybrid EMT state has increased tumor initiating and stem-like properties. Here, we have identified multiple distinct EMT states derived from the human breast cell line, SUM149PT, including three unique intermediate states, possessing distinct migratory, tumor initiating, and metastatic qualities. We have used this model to interrogate the epigenetic landscape of these distinct EMT states in a multi-omics approach, identifying and RUNX2 as relevant in regulating the intermediate state, as well as to develop a novel multiplexed staining approach to evaluate E-M heterogeneity (EMH) and overall EMT score in orthotopic tumors as well as patient tumor samples. This model reveals insights into the complex EMT spectrum of cell states, the networks that control them, and how EMT plasticity contributes to tumor heterogeneity in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172609 | GEO | 2022/02/15

REPOSITORIES: GEO

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Phenotypic heterogeneity driven by plasticity of the intermediate EMT state governs disease progression and metastasis in breast cancer [ATAC-seq]

Project description:The Epithelial-to-Mesenchymal Transition (EMT) is a dynamic cellular program that is frequently used by cancer cells to increase migratory and invasive cell characteristics. It is a key contributor to both heterogeneity and chemo-resistance and metastasis in many solid tumors, including triple negative breast cancer. In particular, the intermediate or hybrid EMT state has increased tumor initiating and stem-like properties. Here, we have identified multiple distinct EMT states derived from the human breast cell line, SUM149PT, including three unique intermediate states, possessing distinct migratory, tumor initiating, and metastatic qualities. We have used this model to interrogate the epigenetic landscape of these distinct EMT states in a multi-omics approach, identifying and RUNX2 as relevant in regulating the intermediate state, as well as to develop a novel multiplexed staining approach to evaluate E-M heterogeneity (EMH) and overall EMT score in orthotopic tumors as well as patient tumor samples. This model reveals insights into the complex EMT spectrum of cell states, the networks that control them, and how EMT plasticity contributes to tumor heterogeneity in breast cancer.

2022-02-15 | GSE172608 | GEO

TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis

Project description:Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity; an EMT/MET axis is critical for metastatic colonization of carcinomas. Unlike epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here we describe the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that microRNA-424 is up-regulated early during a TWIST1/SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Further, microRNA-424 increases motility, decreases adhesion and induces a growth arrest, changes associated with a complete EMT. Patient microRNA-424 levels positively associate with TWIST1/2 and EMT-like gene signatures and is increased in primary tumors versus matched normal breast. However, microRNA-424 is down-regulated in metastases versus matched primary tumors. Correspondingly, microRNA-424 decreases tumor initiation and is post-transcriptionally down-regulated in macrometastases in mice. RNA-seq identified microRNA-424 regulates numerous genes associated with EMT and breast cancer stemness including the novel miR-424 target, TGFBR3, which regulates mesenchymal phenotypes without influencing miR-424 effects on tumor-initiating phenotypes; instead, we show that ERK signaling is critical for such tumor-initiating effects of miR-424. These findings suggest microRNA-424 plays distinct roles downstream of EMT-inducing factors, facilitating earlier stages, but repressing later stages, of metastasis. Examination of mRNA levels in MCF12A human breast cell lines that stably over-expressed miR-424 or an empty vector (EV) control. Each group has three replicates.

2015-02-26 | E-GEOD-54505 | biostudies-arrayexpress

An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

Project description:The Epithelial–Mesenchymal Transition (EMT) and primary ciliogenesis induce stem cell properties in basal Mammary Stem Cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon intermediate EMT transition states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote BBS11-dependent ubiquitination and inactivation of a central signaling node, GLIS2. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the Mammary-Tumor-initiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC biology, mammary gland development, and claudin-low breast cancer formation.

2021-10-05 | GSE173788 | GEO

TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis

2015-02-26 | GSE54505 | GEO

Functional states in tumor-initiating cell differentiation in human colorectal cancer

Project description:Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell mRNA-sequencing (scRNA-seq) of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Targeting transcriptional states associated to cancer cell differentiation might unravel vulnerabilities in human CRC.

2021-05-07 | PXD018230 | Pride

Cell type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition [ATAC-seq]

Project description:Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness and resistance to therapy. The reason why some tumors undergo EMT and other not might reflect intrinsic properties of their cell of origin, although this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show cell type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from intrafollicular epidermis (IFE) are generally well-differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT. Accessible chromatin regions were profiled using ATAC-seq, enriched peak regions were used to infer transcription factor binding sites.

2016-09-01 | E-GEOD-70474 | biostudies-arrayexpress

Single cell analysis of MCF7-V breast carcinoma cell line stably expressing a doxycyline-inducible construct to express ZEB1 in presence of dxycycline.

Project description:The epithelial to mesenchymal transition (EMT) is implicated in the metastatic spread of breast cancer cells. EMT transcription factors (TF) regulate different stages of EMT states. In breast cancers, estrogen receptor α (ERα) maintains the epithelial characteristics of breast tumors and is indispensable for efficient endocrine therapy. In this study we investigate whether and how ZEB1, an EMT-TF affects ERα signaling at early stages of EMT and metastasis. In MCF7-V cells, we performed scRNA-seq to evaluate if ZEB1 modulates cellular heterogeneity at early EMT states in breast cancer cells.

2022-03-14 | GSE173491 | GEO

Regan2022 - Mechanosensitive EMT model with autocrine TGFbeta signaling

Project description:This model is an expansion of the Regan2022 - Mechanosensitive EMT model (MODEL2208050001); it includes a TGFβ signaling module and autocrine signaling in mesenchymal cells. The expanded 150-node (630 link) modular model undergoes EMT triggered by biomechanical and growth signaling crosstalk, or by TGFβ. As its predecessor, this model also reproduces the ability of the core EMT transcriptional network to maintain distinct epithelial, hybrid E/M and mesenchymal states, as well as EMT driven by mitogens such as EGF on stiff ECM. We also reproduce the observed lack of stepwise MET, in that our model's dynamics does not pass through the hybrid E/M state during MET. We show that in the absence of strong autocrine signals such as TGFβ (not included in this version), cells cannot maintain their mesenchymal state in the absence of mitogens, on softer matrices, or at high cell density. In contrast, potent autocrine signaling can stabilize the mesenchymal state in all but very dense monolayers on soft ECM. This expanded model also reproduces the inhibitory effects of TGFβ on proliferation and anoikis resistance in mesenchymal cells, as well as its ability to trigger apoptosis on soft ECM vs. EMT on stiff matrices. The model offers several experimentally testable predictions related to the effect of neighbors on partial vs. full EMT, the tug of war between mitosis and the maintenance of migratory hybrid E/M states, as well as cell cycle defects in dynamic, heterogeneous populations of epithelial, hybrid E/M and mesenchymal cells.

2023-12-13 | MODEL2208050002 | BioModels

Identification of the tumour transition states occurring during EMT [p63 overexpression RNA-seq]

Project description:EMT in cancer has been associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary process, EMT occurs through distinct intermediate states. However,direct in vivo evidence supporting this possibility is still lacking. By screening a large panel of cell surface markers, we identified the existence of multiple tumour subpopulations associated with different EMT stages from epithelial to completely mesenchymal states passing through intermediate hybrid states in skin and mammary primary tumours. Although all EMT subpopulations presented similar tumour propagating cell capacity, they displayed different , invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes defined by RNA-seq and ATAC-seq identified the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulateEMT transition states.

2018-02-15 | GSE110586 | GEO

Identification of the tumour transition states occurring during EMT [RNA-seq]

2018-02-15 | GSE110585 | GEO

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