Quantifying Cancer Epithelial-Mesenchymal Plasticity and Its Association with Stemness and Immune Response

Jia, Dongya; Li, Xuefei; Bocci, Federico; Tripathi, Shubham; Deng, Youyuan; Jolly, Mohit Kumar; Onuchic, José N.; Levine, Herbert

doi:10.20944/preprints201904.0206.v1

Cited by 30 publications

(22 citation statements)

References 72 publications

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“…Thus, phenotypic plasticity -the ability of disseminating cancer cells to adapt their phenotypes reversibly in response to their dynamic microenvironments -has been regarded as a hallmark of metastasis-initiating cells [4]. Phenotypic plasticity exists at multiple interconnected axes -a) epithelial-mesenchymal plasticity (EMP), b) metabolic plasticity, and c) plasticity between a cancer stem cell (CSC) and non-CSC state (i.e., stemness), among others [5]. Understanding such functional inter-dependencies from a dynamical systems level can lead to deciphering the organizing principles of underlying regulatory network modules and, eventually, therapeutic advances that can target cancer cell adaptability/plasticity [6,7].…”

Section: Introductionmentioning

confidence: 99%

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Pasani

Sahoo

Jolly

2020

Preprint

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Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are a) their ability to dynamically move along the epithelial-hybrid-mesenchymal spectrum and b) their tumor-initiation potential or stemness. With increasing functional characterization of hybrid epithelial /mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parameter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to 'pure' epithelial or mesenchymal states. We also integrate multiple 'phenotypic stability factors' (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro - such as OVOL1/2, GRHL2, and NRF2 - with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) being essential for tumor-initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT and stemness networks.

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Section: Introductionmentioning

confidence: 99%

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Pasani

Sahoo

Jolly

2020

Preprint

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“…1a and b). Several studies support the association between EMT and immune cell escape [36,37]. Moreover, a plethora of genes and signals support stem-cell support pathways such as Wnt, TGF-β, and NOTCH [6].…”

Section: Discussionmentioning

confidence: 93%

Metastasis progression through the interplay between the immune system and Epithelial-Mesenchymal-Transition in circulating breast tumor cells

Khoshbakht

Jamalkandi

Masudi-Nejad

2020

Preprint

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BackgroundCirculating tumor cells (CTCs) are the critical initiator of systemic dissemination of cancer, contributing to distant metastasis formation. The metastatic cascades rely on the fundamental roles of different types of CTCs. In which the dual immune responses and epithelial-mesenchymal-transition (EMT) are of two metastasis-driving phenomena and require more molecular assessments.MethodsIn this study, we investigated the transcriptomic modular pattern of single/cluster circulating tumor cells (CTCs). The co-expression analysis implemented, and we could detect two metastatic subnetworks indicating the immune responses and EMT in CTCs. Furthermore, a directed subnetwork identified in the KEGG database. The metastatic potential of subnetworks assessed and validated by classification methods on primary tumors. And, we could fit risk models to distant-metastasis survival of patients.ResultsOur results show the crosstalk among EMT, immune system, menstrual cycles, and stemness in CTCs. In which, fluctuation of menstrual cycles (hormone-related signals) is a new detected pathway in CTCs in breast cancer. The immune SVM model showed high metastatic potential in classifying patients metastatic/non-metastatic groups (accuracy, sensitivity, and specificity scores are 78%). The distant-metastasis free survival model could be used to stratify patients into low, medium, and high-risk groups. Finally, PTCRA, F13A1, LAT, ICAM2, and SNRPC are novel detected biomarkers in breast cancer.ConclusionIn conclusion, different types of CTCs, including cluster/single cells, are metastasis-leading elements in breast cancer. In which, individual assessment of their intrinsic biological properties may assist elucidating metastasis-related mechanisms. These findings may apply to develop superior treatments in the clinic.

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“…Of note, several studies supported the association between EMT and immune cell escape of cancer cells [25,26]. Moreover, a plethora of genes and signals support stemness pathways such as Wnt, TGF-β, and NOTCH in CTCs [10].…”

Section: Distant Metastasis-free-survival and Overall Survival Analmentioning

confidence: 95%

Metastasis Progression Through the Interplay Between the Immune System and Epithelial-mesenchymal-transition in Circulating Breast Tumor Cells

Khoshbakht

Jamalkandi²,

Masudi-Nejad

2020

Preprint

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BackgroundCirculating tumor cells (CTCs) are the critical initiators of distant metastasis formation. In which, the reciprocal interplay among different metastatic pathways which promote survival of CTCs, is not well introduced, using network approaches. CTC cells include single and cluster cells, in which cluster cells revealed 23-50 fold more metastatic potentials.Here, to investigate the unknown pathways of single/cluster CTCs, the co-expression network reconstructed, using WGCNA (Weighted Correlation Network Analysis) method. Having used the hierarchical clustering, we detected the Immune-response and EMT subnetworks. The metastatic potential of genes was assessed and validated through the support vector machine (SVM), neural network, and decision tree methods on two external datasets. To identify the active signaling pathways in CTCs, we reconstructed a casual network. The Log-Rank test and Kaplan-Meier curve were applied to detect prognostic gene signatures for metastasis-free survival. Finally, a predictive model was developed for metastasis risk of patients, using VIF-stepwise feature selection. ResultsOur results showed the crosstalk among EMT, the immune system, menstrual cycles, and the stemness pathway in CTCs. In which, fluctuation of menstrual cycles is a new detected pathway in breast cancer CTCs. The reciprocal association between immune responses and EMT was identified in single/cluster CTCs. The SVM model indicated a high metastatic potential of EMT subnetwork (accuracy, sensitivity, and specificity scores were 87%). The distant-metastasis-free-survival model was identified to predict patients’ metastasis risks. (c-index=0.8). Finally, novel metastatic biomarkers including PTCRA, F13A1, ICAM2, and SNRPC were detected in breast cancer.Conclusions In conclusion, the reciprocal interplay among critical pathways in CTCs enhances their survival and metastatic potentials. Such findings may help to develop more precise predictive metastatic-risk models or detect novel biomarkers.

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Quantifying Cancer Epithelial-Mesenchymal Plasticity and Its Association with Stemness and Immune Response

Cited by 30 publications

References 72 publications

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology

Metastasis progression through the interplay between the immune system and Epithelial-Mesenchymal-Transition in circulating breast tumor cells

Metastasis Progression Through the Interplay Between the Immune System and Epithelial-mesenchymal-transition in Circulating Breast Tumor Cells

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