Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Jan 3

PMID 34975907

Citations 37

Authors

Sarthak Sahoo

Sonali Priyadarshini Nayak

Kishore Hari

Prithu Purkait

Susmita Mandal

Akash Kishore

Herbert Levine

Mohit Kumar Jolly

Affiliations

Soon will be listed here.

Abstract

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our simulations for the network consisting of SLUG, ZEB1, miR-200, CDH1 and PD-L1, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis.

Citing Articles

Accumulation of CD38 in Hybrid Epithelial/Mesenchymal Cells Promotes Immune Remodeling and Metastasis in Breast Cancer.

Visal T, Bayraktar R, den Hollander P, Attathikhun M, Zhou T, Wang J Cancer Res. 2025; 85(5):894-911.

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Endosomal pH is an evolutionarily conserved driver of phenotypic plasticity in colorectal cancer.

Prasad H, Bv H, Subbalakshmi A, Mandal S, Jolly M, Visweswariah S NPJ Syst Biol Appl. 2024; 10(1):149.

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Phenotypic Plasticity and Cancer: A System Biology Perspective.

Subbalakshmi A, Ramisetty S, Mohanty A, Pareek S, Do D, Shrestha S J Clin Med. 2024; 13(15).

PMID: 39124569 PMC: 11313222. DOI: 10.3390/jcm13154302.

Cell-state transitions and density-dependent interactions together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity.

Jain P, Kizhuttil R, Nair M, Bhatia S, Thompson E, George J iScience. 2024; 27(7):110310.

PMID: 39055927 PMC: 11269952. DOI: 10.1016/j.isci.2024.110310.

Increased prevalence of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer.

Sahoo S, Ramu S, Nair M, Pillai M, San Juan B, Milioli H iScience. 2024; 27(7):110116.

PMID: 38974967 PMC: 11225361. DOI: 10.1016/j.isci.2024.110116.

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