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

• Cancer stem cell plasticity intersects with EMT to determine therapeutic resistance.
• Co-treatment with TGFβ and RA enriches a plastic and drug resistant cancer stem cell sub-population for therapeutic testing.
• Thapsigargin specifically targets the plastic and drug resistant cancer stem cell sub-population.Cancer cells have the ability to switch between different identities that enhance their ability to proliferate and spread. In this report, we demonstrate that only some cancer cells possess this special ability to switch identity, and that these cells can resist current cancer therapies. We develop a method to enrich the cancer cells with this special ability, so that new drugs can be tested on them, and then use this method to identify a drug that can target these cells. These dangerous cells must be eradicated to enable long-term patient survival, and these are therefore significant findings for human health.

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.