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

Abstract

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. Significance: This work provides novel insights into c-Met-PLXDC2 signaling in radioresistance-associated aggressiveness and suggests a new mechanism-informed therapeutic strategy to overcome failure of radiotherapy in patients with HNSCC.

HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer

“…When RT is delivered to a tumor, it can have both direct and indirect effects on cancer cell metabolism, including glycolysis ( 18 ). In response to RT-induced DNA damage, cancer cells activate various stress responses, including changes in their metabolism.…”

“…Secondary antibodies were purchased from Invitrogen (Carlsbad, CA). Cell proliferation, viability, colony formation, and Western blot assays were carried out as previously described ( 18 , 43 ).…”

“…This metabolic rewiring allows cancer cells to maintain high proliferation rates and survive under stressful conditions such as hypoxia or nutrient deprivation ( 16 , 17 ). RT is often used as a first-line treatment for HNSCC, either alone or in combination with other treatments such as chemotherapy or surgery ( 18 ). However, development of radioresistance or low treatment efficacy in HNSCC remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades ( 19 ).…”

Evaluation of [18F]AlF-EMP-105 for Molecular Imaging of C-Met

“…Apart from these, accelerated approval and breakthrough therapy designation (BTD) were granted, respectively, for Amivantamab and telisotuzumab vedotin for the treatment of c-Met-overexpressing non-small cell lung cancer (NSCLC) [ 18 , 19 ], signifying the importance of c-Met as a biomarker. The MET/HGF pathway also positively regulates cancer stem cell enrichment and tumour aggressiveness due to stem cell-related resistance to therapy [ 14 , 20 ]. In this regard, the development of probes for c-Met imaging would further aid in improving diagnosis, patient selection, and assessment of patient response to c-Met targeted therapy.…”

“…Pharmaceutics 2023, 15, x FOR PEER REVIEW 2 of 14 enrichment and tumour aggressiveness due to stem cell-related resistance to therapy. [14,20]. In this regard, the development of probes for c-Met imaging would further aid in improving diagnosis, patient selection, and assessment of patient response to c-Met targeted therapy.…”