Comprehensive Genomic Profiling of Patient-matched Head and Neck Cancer Cells: A Preclinical Pipeline for Metastatic and Recurrent Disease

Abstract

: Metastases and tumor recurrence have a major prognostic impact in head and neck squamous cell carcinoma (HNSCC); however, cellular models that comprehensively characterize metastatic and recurrent HNSCC are lacking. To this end, we obtained genomic, transcriptomic, and copy number profiles of the UM-SCC cell line panel, encompassing patient-matched metastatic and recurrent cells. UM-SCC cells recapitulate the most prevalent genomic alterations described in HNSCC, featuring common TP53, PI3K, NOTCH, and Hippo pathway mutations. This analysis identified a novel F977Y kinase domain PIK3CA mutation exclusively present in a recurrent cell line (UM-SCC14B), potentially conferring resistance to PI3K inhibitors. Small proline-rich protein 2A (SPRR2A), a protein involved in epithelial homeostasis and invasion, was one of the most consistently downregulated transcripts in metastatic and recurrent UM-SCC cells. Assessment of SPRR2A protein expression in a clinical cohort of patients with HNSCC confirmed common SPRR2A downregulation in primary tumors (61.9% of cases) and lymph node metastases (31.3%), but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy (HR 2.81; 95% CI, 1.16-6.79; = 0.02). These results suggest that SPRR2A plays a dual role in invasion and therapeutic resistance in HNSCC, respectively through its downregulation and overexpression. IMPLICATIONS: The current study reveals translationally relevant mechanisms underlying metastasis and recurrence in HNSCC and represents an adjuvant tool for preclinical research in this disease setting. Underlining its discovery potential this approach identified a PIK3CA-resistant mutation as well as SPRR2A as possible theragnostic markers.

Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma

“…The effect of PI3Ki on proliferation was significantly enhanced when CQ was added to the treatment. We performed the same experiment with a panel of HPV-negative HNSCC cell lines harboring the most common PIK3CA alterations ( Figure 2 D), but all mutated for TP53 [ 40 , 41 , 42 , 43 , 44 ]. TP53 mutated cell lines represent 86% of HPV-negative HNSCC cases [ 3 ], and a study found TP53 mutations in 95% of metastatic HNSCC [ 45 ].…”

ProtRank: bypassing the imputation of missing values in differential expression analysis of proteomic data

“…1 which shows the distributions of positive values in pairwise comparisons involving zero and a positive count. The distributions are shown for two different datasets: A transcriptomic dataset analyzed in [14] and a phosphoproteomic dataset analyzed in [Koch et al, manuscript in preparation] (see “Description of the transcriptomic data” section and “Description of the phosphoproteomic data” section for the datasets’ descriptions). To allow for easy comparison, the counts are scaled by the dataset’s median in both cases.…”

“…Description of the transcriptomic data The transcriptomic data from head and neck squamous cell carcinoma patient-derived cell lines have been originally analyzed in [14] (the authors have used edgeR for the differential expression analysis). Out of the 15 cell lines used in that study, we keep eight of them for pairwise differential expression analysis: Cell lines UM-SCC-11A, -14A, -74A, and -81A from primary tumors, and cell lines UM-SCC-11B, -14B, -74B, and -81B from recurrent tumors.…”

Serum Small Proline-Rich Protein 2A (SPRR2A) Is a Noninvasive Biomarker in Gastric Cancer

“…As discussed by Nisa et al, SPRR2A played a dual role in invasion and therapeutic resistance in head and neck squamous cell carcinoma. High expression of SPRR2A in lymph node metastases was, along with the nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy [ 14 ]. In the present study, serum SPRR2A expression in patients with GC, gastritis, and colorectal cancer and in healthy people was detected by ELISA.…”