Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

TLDR

Cancer stem cells drive tumor spread and therapeutic resistance and can switch between epithelial and post‑EMT states via EMT and MET. The study demonstrates that increased phenotypic plasticity underlies heightened CSC therapeutic resistance in oral squamous cell carcinoma across both epithelial and post‑EMT sub‑populations. By treating cells with TGFβ and retinoic acid to enrich the plastic sub‑population, the authors selectively targeted these cells with the ER‑stress/autophagy inhibitor Thapsigargin. Plastic post‑EMT CSCs, identified by a CD44^highEpCAM^low/−CD24^+ profile, show markedly enhanced therapeutic resistance, and the authors’ enrichment method offers a platform for developing chemotherapeutics that eliminate CSCs.

Abstract

Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/−CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.