Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma

Abstract

Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the human papillomavirus (HPV+)-driven subtype is the fastest rising cancer in North America. Although most cases of HPV+ HNSCC respond favorably to the treatment via surgery followed by radiochemotherapy, up to 20% recur with a poor prognosis. The molecular and cellular mechanisms of recurrence are not fully understood. Methods To gain insights into the mechanisms of recurrence and to inform patient stratification and personalized treatment, we compared the proteome and phosphoproteome of recurrent and non-recurrent tumors by quantitative mass spectrometry. Results We observe significant differences between the recurrent and non-recurrent tumors in cellular composition, function, and signaling. The recurrent tumors are characterized by a pro-fibrotic and immunosuppressive tumor microenvironment (TME) featuring markedly more abundant cancer-associated fibroblasts, extracellular matrix (ECM), neutrophils, and suppressive myeloid cells. Defective T cell function and increased epithelial-mesenchymal transition potential are also associated with recurrence. These cellular changes in the TME are accompanied by reprogramming of the kinome and the signaling networks that regulate the ECM, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Conclusions In addition to providing systems-level insights into the molecular basis of recurrence, our work identifies numerous mechanism-based, candidate biomarkers and therapeutic targets that may aid future endeavors to develop prognostic biomarkers and precision-targeted treatment for recurrent HPV+ HNSCC.

Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

“…That said, T-cell infiltration is a continuous variable across patient cohorts. A recent proteomics study reported significantly reduced expression of T-cell markers in HPV(+) tumors that would eventually recur, compared to those that did not recur [52]. Our data suggest that a small fraction of HPV(+) tumors have low T-cell infiltration comparable to that of typical HPV(-) tumors.…”

The molecular characteristics of recurrent/metastatic HPV‐positive head and neck squamous cell carcinoma: A systematic review of the literature

“…Upon stimulation by its ligands, several downstream signalling pathways are activated that promote proliferation, growth, and survival, also including angiogenesis and metastasis. Expression and phosphorylation of EGFR have been identified as significantly increased in recurrent HPV‐positive HNSCC 39 . Cetuximab, a monoclonal antibody targeting EGFR 's extracellular domain, has obtained approval more than a decade ago for the treatment of recurrent/metastatic HNSCC.…”

“…Expression and phosphorylation of EGFR have been identified as significantly increased in recurrent HPV-positive HNSCC. 39 Cetuximab, a monoclonal antibody targeting EGFR's extracellular domain, has obtained approval more than a decade ago for the treatment of recurrent/metastatic HNSCC. However, response rates to EGFR-targeted therapies with monoclonal antibodies or tyrosine kinase inhibitors in HNSCC remain unsatisfactory, potentially due to persistently active downstream pathways serving as alternatives.…”

Disulfidptosis features and prognosis in head and neck squamous cell carcinoma patients: unveiling and validating the prognostic signature across cohorts

“…Several studies have reported the prognostic value of the MYH family genes MYL1, MYL2, MYH1, MYH2, and MYH7, which are unfavorable prognostic markers in HNSCC and might promote CD4 + T-cell activation (Li et al 2023 ; Ju et al 2023 ). The level of phosphorylated MYH2-Y1381 is reportedly significantly lower in recurrent HNSCC patients than in primary patients (Kaneko et al 2022 ). Hub genes might be pivotal components that accelerate the progression of HNSCC.…”