Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

Gupta, Pallavi; Pastushenko, Ievgenia; Skibinski, Adam; Blanpain, Cédric; Kuperwasser, Charlotte

doi:10.1016/j.stem.2018.11.011

Cited by 463 publications

(430 citation statements)

References 136 publications

(203 reference statements)

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“…Therefore, TamR cells displayed a gene expression profile featured for EMT and hybrid epithelial/mesenchymal phenotypes. Consistent with TamR phenotype, cancer cells at a hybrid epithelial/mesenchymal state are often more invasive or acquire therapy resistance 3,27 .…”

Section: Endocrine Resistance Is Associated With Plasticity-enhancingmentioning

confidence: 96%

“…Cancer progression, by which cancer cells adjust themselves to achieve resistance to targeted therapies, is a persistent challenge in cancer treatment. Extensive studies on this phenomenon have revealed that cancer cells can escape targeted therapy through one of the following mechanisms: mutation of the drug targets 1 ; activation of alternate pathways that restore the downstream targets that are inhibited by initial drug blockade 2 ; a recently identified plasticity mechanism by which cell phenotypic plasticity drives therapy resistance [3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Zhang

Xue

et al. 2019

Preprint

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Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.However, when patients with ERα-positive breast cancer receive endocrine therapies for a period of 5 years, more than 30% of these patients eventually develop resistance and disease recurrence 9, 10 . As loss of ERα expression during therapies or metastatic progression is only found in ≤10% of patients 9 , this hormone-receptor pathway remains a major research focus for additional targeted therapies.Substantial evidence suggests that changes of components along the ERα axis, such as mutations or altered expression of ERα itself or ERα-interacting cofactors, may reprogram the ERα-mediated transcriptome that underlie the development of endocrine resistance [11][12][13] . Differential ERα binding is 5 also associated with clinical breast cancer progression 14 . However, the underlying molecular mechanisms of transcriptome transitions mediated by ERα during breast cancer progression and endocrine resistance are not well known.Enhancers are important distal DNA regulatory elements that control temporal-or spatial-specific gene expression patterns during development and other biological processes [15][16][17] . Dysregulation of enhancer function is involved in many diseases, particularly in cancers. Our previous genome-wide ChIP-seq studies have revealed that E 2 /ERα regulates its target gene expression program primarily through binding at distal enhancers to dictate cell growth and endocrine response 18,19 . Emerging evidence has implicated the link of epigenetic alterations of ERα-bound enhancers to hormone resistance and cancer invasion 14,20 . Thus, investigating oncogenic mechanisms that lead to the alterations of the ERα cistrome is critical for both understanding cancer progression and identifying of potential new cancer therapies.In this study, we compared matched control and resistant cells lin...

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Section: Endocrine Resistance Is Associated With Plasticity-enhancingmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Zhang

Xue

et al. 2019

Preprint

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“…Recent lines of evidence suggest that these distinct steps are not supported by a unique cell state. In contrast to the classic view of EMT as a binary process with two exclusive phenotypes, either fully epithelial of fully mesenchymal, the program entails epithelial cells entering into a variety of intermediate states with different functions and properties (Gupta et al, 2019;Nieto et al, 2016;Pastushenko and Blanpain, 2019). Consistent with this notion, cancer cells exhibiting a hybrid epithelial-mesenchymal phenotype have been identified in both primary tumors and at sites of dissemination (Aceto et al, 2014;Baccelli et al, 2013;Kröger et al, 2019;Yu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

Margaron

Nagai

Guyon

et al. 2019

Preprint

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Potential metastatic cells can dissociate from a primary breast tumor by undergoing an epithelial-to-mesenchymal transmission (EMT). Recent work has revealed that cells in intermediate states of EMT acquire an augmented capacity for tumor-cell dissemination. These states have been characterized by molecular markers, but the structural features and the cellular mechanisms that underlie the acquisition of their invasive properties are still unknown. Using human mammary epithelial cells, we generated cells in intermediate states of EMT through the induction of a single EMT-inducing transcription factor, ZEB1, and cells in a mesenchymal state by stimulation with TGFβ. In stereotypic and spatially-defined culture conditions, the architecture, internal organization and mechanical properties of cells in the epithelial, intermediate and mesenchymal state were measured and compared. We found that the lack of intercellular cohesiveness in epithelial and mesenchymal cells can be detected early by microtubule destabilization and the repositioning of the centrosome from the cell-cell junction to the cell center. Consistent with their high migration velocities, cells in intermediate states produced low contractile forces compared with epithelial and mesenchymal cells. The high contractile forces in mesenchymal cells powered a retrograde flow pushing the nucleus away from cell adhesion to the extracellular matrix. Therefore, cells in intermediate state had structural and mechanical properties that were distinct but not necessarily intermediate between epithelial and mesenchymal cells. Based on these observations, we found that a panel of triple-negative breast cancer lines had intermediate rather than mesenchymal characteristics suggesting that the structural and mechanical properties of the intermediate state are important for understanding tumor-cell dissemination.

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“…Here, we downloaded five datasets of colon cancer derived from Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/), which consisted of the transcriptome profile data of 988 samples. To establish a lncRNAs‐based model that could be used for improving the relapse risk prediction and tailoring therapies, we specially identified lncRNAs that were significantly associated with both cancer prognosis and biological processes including angiogenesis, hypoxia, TGFβ signalling and epithelial‐mesenchymal transformation (EMT), which have been well‐studied in multiple solid tumours, and defined as important stroma‐related factors mediating tumour metastasis and drug resistance, including in colon cancer …”

Section: Introductionmentioning

confidence: 99%

A stroma‐related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early‐stage colon cancer

Zhou

Sun

Zheng

et al. 2020

J Cellular Molecular Medi

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The heterogeneity in prognoses and chemotherapeutic responses of colon cancer patients with similar clinical features emphasized the necessity for new biomarkers that help to improve the survival prediction and tailor therapies more rationally and precisely. In the present study, we established a stroma‐related lncRNA signature (SLS) based on 52 lncRNAs to comprehensively predict clinical outcome. The SLS model could not only distinguish patients with different recurrence and mortality risks through univariate analysis, but also served as an independent factor for relapse‐free and overall survival. Compared with the conventionally used TNM stage system, the SLS model clearly possessed higher predictive accuracy. Moreover, the SLS model also effectively screened chemotherapy‐responsive patients, as only patients in the low‐SLS group could benefit from adjuvant chemotherapy. The following cell infiltration and competing endogenous RNA (ceRNA) network functional analyses further confirmed the association between the SLS model and stromal activation‐related biological processes. Additionally, this study also identified three phenotypically distinct colon cancer subtypes that varied in clinical outcome and chemotherapy benefits. In conclusion, our SLS model may be a significant determinant of survival and chemotherapeutic decision‐making in colon cancer and may have a strong clinical transformation value.

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Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

Cited by 463 publications

References 136 publications

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

A stroma‐related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early‐stage colon cancer

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