Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer

by Selleckchem | Dec 27 2023

Radiotherapy plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSCC), yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. Here we report that radioresistant HNSCC cells exhibit increased tumor aggressiveness. Using unbiased proteome profiler antibody arrays, we identify that upregulation of c-Met phosphorylation is one of the critical mechanisms for radioresistance in HNSCC cells. We further uncover that radioresistance-associated HNSCC aggressiveness is effectively exacerbated by c-Met but is suppressed by its genetic knockdown and pharmacologic inactivation. Mechanistically, the resulting upregulation of c-Met promotes elevated expression of plexin domain containing 2 (PLXDC2) through activating ERK1/2-ELK1 signaling, which in turn modulates cancer cell plasticity by epithelial-mesenchymal transition (EMT) induction and enrichment of the cancer stem cell (CSC) subpopulation, leading to resistance of HNSCC cells to radiotherapy. Depletion of PLXDC2 overcomes c-Met-mediated radioresistance through reversing the EMT progress and blunting the self-renewal capacity of CSCs. Therapeutically, the addition of SU11274, a selective and potent c-Met inhibitor, to radiation induces tumor shrinkage and limits tumor metastasis to lymph nodes in an orthotopic mouse model. Collectively, these significant findings not only demonstrate a novel mechanism underpinning radioresistance-associated aggressiveness but also provide a possible therapeutic strategy to target radioresistance in patients with HNSCC.

Comments:

This report underscores the complexity of radioresistance in head and neck squamous cell carcinoma (HNSCC) and its relationship with tumor aggressiveness. The study highlights the role of c-Met phosphorylation as a key mechanism driving radioresistance in HNSCC cells. Elevated c-Met levels contribute to the activation of pathways that promote aggressiveness, including the upregulation of PLXDC2 through ERK1/2-ELK1 signaling.

The findings suggest that targeting c-Met or its downstream effectors, such as PLXDC2, could potentially reverse radioresistance. Inhibiting c-Met with SU11274 alongside radiation treatment shows promise in reducing tumor size and limiting metastasis in animal models.

Understanding the molecular pathways that govern radioresistance is crucial for developing more effective therapies for HNSCC. By disrupting these pathways, such as by using targeted inhibitors like SU11274, there's potential to enhance the effectiveness of radiotherapy and mitigate the challenges posed by radioresistance in treating HNSCC.

This study not only sheds light on the mechanisms driving radioresistance-associated aggressiveness but also offers a promising avenue for therapeutic interventions that could benefit patients with HNSCC.