Epidermal Growth Factor Receptor Inhibition’s Effects on Invasion within Head and Neck Squamous Cell Carcinomas

Abstract

Objective: Targeted therapies can have mixed effects on cancer progression by limiting growth while simultaneously potentiating invasion and metastasis. Here we test the role of a mesenchymal-like subpopulation (MLSP) of head and neck squamous cell carcinoma (HNSCC) cells in altering pattern of invasion (POI) during epidermal growth factor receptor (EGFR) inhibition.

Method: The contribution of MSLP cells to POI was evaluated in collagen-embedded spheroids and patient-derived xenografts (PDXs). MLSPs were identified by immunostaining for vimentin expression, E-cadherin loss, and additional markers of epithelial to mesenchymal transition. Spheroids and xenografts undergoing anti-EGFR treatment were evaluated for altered MLSP size, distribution, and invasion.

Results: MLSP cells were rare or absent in PDXs whose HNSCCs of origin contained less aggressive, pushing POIs. In contrast, abundant MLSP cells were seen in PDXs from tumors with highly infiltrative POIs. In collagen-embedded spheroids, a pushing POI was mediated by collective migration of E-cadherin-positive cells, while infiltrative POIs arose from mesenchymal migration of MLSP cells. EGFR inhibition in spheroids produced a more aggressive POI by selectively targeting the epithelial subpopulation, which expressed higher levels of the receptor. Similarly, cetuximab treatment of xenografts enriched MLSP cells, which contributed to a more infiltrative invasion pattern in residual tumors.

Conclusion: Different HNSCC POIs arise from distinct migratory mechanisms used by E-cadherin-positive versus MLSP tumor cells. Cetuximab therapy potentiates the capacity of MLSP cells to produce an infiltrative POI. Anti-EGFR therapy may therefore have disparate effects in altering progression of 2 HNSCC sub-types, defined by presence or absence of MLSP cells.