Zamuner, F. T. | bioRxiv Science

bioRxiv2026

scRNA-seq and genomics analyses reveal key mechanisms of inverted papilloma-associated sinonasal squamous cell carcinoma malignant transformation

Sinonasal inverted papilloma (IP) carries a 10% risk of malignant transformation to IP-associated sinonasal squamous cell carcinoma (IP-SNSCC), yet the molecular and immune drivers of this progression remain poorly defined. This study integrates single-cell RNA sequencing, multiplexed spatial proteomics, whole-exome sequencing, and functional assays across IP and IP-SNSCC cohorts to define mechanisms of malignant transformation. Respiratory epithelial basal cells are identified as the putative cell of origin, with progression marked by recurrent CDKN2A loss and TP53 mutations. Spatial profiling reveals immune reorganization at the lesional interface in IP-SNSCC, characterized by enrichment of alternatively activated M2 macrophages. CXCL14 is shown to directly induce an immunosuppressive myeloid phenotype that suppresses T-cell IFN{gamma} production through an IDO-pathway-dependent mechanism. Integration of these multimodal datasets defines a previously unrecognized CXCL14-IDO mechanism that constrains anti-tumor immunity at the tumor-stroma interface. These findings establish IDO-targeted immunomodulation as a rational adjuvant strategy and provide a comprehensive molecular framework for understanding IP-SNSCC pathogenesis.

genomics↗

bioRxiv2024

Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma

Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C, UBXN11, AP3S1, MT-ND4, and MT-ND5. Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC. One Sentence SummaryThis study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.

cancer biology↗