Distinct contributions of partial and full EMT to breast cancer malignancy

Lüönd, Fabiana; Sugiyama, Nami; Bill, Ruben; Bornes, Laura; Hager, C.; Tang, Fengyuan; Santacroce, Natascha; Beisel, Christian; Ivánek, Robert; Bürglin, Thomas R.; Tiede, Stefanie; Rheenen, Jacco van; Christofori, Gerhard

doi:10.1016/j.devcel.2021.11.006

Cited by 212 publications

(168 citation statements)

References 78 publications

(123 reference statements)

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“…In this phase diagram, the IFNγ-induced leftward shift is clearly visible. Additionally, it shows that the total range of SNAIL1 for which the hybrid E/M phenotype, a particularly aggressive EMT phenotype (Lüönd et al, 2021, andreviewed in Jolly, Somarelli, et al, 2018), can (co-)exist is unaffected.…”

Section: Ifnγ Promotes the Occurrence Of Emtmentioning

confidence: 93%

Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor progression

Burger

Nesenberend

Lems

et al. 2022

Preprint

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Epithelial-Mesenchymal Transition (EMT) and immunoevasion through upregulation of Programmed Death-Ligand 1 (PD-L1) are important drivers of cancer progression. While EMT has been proposed to facilitate PD-L1-mediated immunosuppression, the molecular mechanisms of their interaction remain obscure. Here we provide insight into these mechanisms by proposing a mathematical model that describes the crosstalk between EMT and Interferon gamma (IFNγ)-induced PD-L1 expression. Our model shows that via interaction with microRNA-200 (miR-200), the multistability of the EMT regulatory circuit is mirrored in the PD-L1 levels, which are further amplified by IFNγ stimulation. This IFNγ-mediated effect is most prominent for cells in a fully mesenchymal state, and less strong for those in an epithelial or partially mesenchymal state. Additionally, bi-directional crosstalk between miR-200 and PD-L1 implies that IFNγ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and that IFNγ presence accelerates EMT and decelerates Mesenchymal-Epithelial Transition (MET). Overall, our model agrees with published findings and provides insight into possible mechanisms behind EMT-mediated immune-evasion; and primary, adaptive, or acquired resistance to immunotherapy. Our model can be used as a starting point to explore additional crosstalk mechanisms, as an improved understanding of these mechanisms is indispensable for developing better diagnostic and therapeutic options for cancer patients.

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Section: Ifnγ Promotes the Occurrence Of Emtmentioning

confidence: 93%

Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor progression

Burger

Nesenberend

Lems

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…An immunofluorescence microscopy assay for cytoskeletal remodeling elements [ 76 ] has been successfully implemented as a readout for EMT disruption to screen a panel of transcription factor-targeting siRNAs to determine transcriptional nodes that control EMT [ 77 ], which can be useful for easy drug treatment and screening for future testable therapeutics targeting EMT. Moreover, recent work has combined fluorescent lineage tracing with intravital live microscopy to visualize and trace early and late EMT states in the primary tumor and metastatic sites, providing a much needed look inside the dynamic processes of tumor progression and EMT [ 13 ]. Combined immunofluorescence with other techniques, such as cell morphology or single-cell segmentation, has distinct advantages over bulk flow or sequencing by maintaining tumor architecture and spatial organization in the tissue.…”

Section: Immunohistochemistry and Fluorescencementioning

confidence: 99%

“…The presence and role of a variety of hybrid EMT states in disease progression and metastasis remains a lynchpin in EMT-based therapies. Current evidence suggests that rather than relying solely on an MET to revert from a fully mesenchymal state, metastasis may result from the high plasticity and adaptability of the intermediate or hybrid states [ 12 , 13 ], as observed by the presence of intermediate circulating tumor cell clusters (CTCs clusters) [ 14 , 15 ]. Regardless of a clear-cut mechanism, which is still currently in debate, the presence of an intermediate state appears to be critical to the formation of metastasis, either through plasticity or as a transitional state.…”

Section: Introductionmentioning

confidence: 99%

Quantifying the Epithelial-to-Mesenchymal Transition (EMT) from Bench to Bedside

Brown

Muller

Pattabiraman

2022

Cancers

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The epithelial-to-mesenchymal transition (EMT) and its reversal, the mesenchymal-to-epithelial transition (MET) are critical components of the metastatic cascade in breast cancer and many other solid tumor types. Recent work has uncovered the presence of a variety of states encompassed within the EMT spectrum, each of which may play unique roles or work collectively to impact tumor progression. However, defining EMT status is not routinely carried out to determine patient prognosis or dictate therapeutic decision-making in the clinic. Identifying and quantifying the presence of various EMT states within a tumor is a critical first step to scoring patient tumors to aid in determining prognosis. Here, we review the major strides taken towards translating our understanding of EMT biology from bench to bedside. We review previously used approaches including basic immunofluorescence staining, flow cytometry, single-cell sequencing, and multiplexed tumor mapping. Future studies will benefit from the consideration of multiple methods and combinations of markers in designing a diagnostic tool for detecting and measuring EMT in patient tumors.

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“…Cancer cells can also revert from P-EMT states to epithelial states through mesenchymal-epithelial transition (MET) (Beerling et al ., 2016; Jolly et al, 2017; Reichert et al ., 2018). This spectrum of heterogenous EMT states may be associated with differences in epithelial plasticity and cell migration, thereby influencing tumor progression, metastasis and response to treatment (Aiello et al ., 2018; Lüönd et al, 2021). Targetable cell intrinsic mechanisms that drive either P-EMT or C-EMT remain elusive.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 induced S100 family protein expression is associated with epithelial to mesenchymal transition states and poor survival in pancreatic cancer

Low

Fung

Gao

et al. 2022

Preprint

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Epithelial-mesenchymal transition (EMT) is a continuum that includes epithelial, partial EMT (P-EMT) and mesenchymal states, each of which are associated with cancer progression, invasive capabilities and ultimately metastasis. We have employed a lineage traced sporadic model of pancreatic cancer to generate a murine organoid biobank from primary and secondary tumors, including sublines that have undergone P-EMT and complete EMT (C-EMT). Using an unbiased proteomics approach, we found that the morphology of the organoids predicts the EMT state, with solid organoids associated with a P-EMT signature. We also observed that exogenous TGF-beta1 induces a solid organoid morphology that is associated with changes in the S100 family, C-EMT and the formation of high-grade tumors. S100A4 may represent a useful biomarker to predict EMT state, disease progression and outcome for pancreatic cancer patients.

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Distinct contributions of partial and full EMT to breast cancer malignancy

Cited by 212 publications

References 78 publications

Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor progression

Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor progression

Quantifying the Epithelial-to-Mesenchymal Transition (EMT) from Bench to Bedside

TGF-β1 induced S100 family protein expression is associated with epithelial to mesenchymal transition states and poor survival in pancreatic cancer

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