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  3. Single-Nucleus Multi-Omics Reveals Hypoxia-Driven Angiogenic Programs and Their Epigenetic Control in Sinonasal Squamous Cell Carcinoma

Single-Nucleus Multi-Omics Reveals Hypoxia-Driven Angiogenic Programs and Their Epigenetic Control in Sinonasal Squamous Cell Carcinoma

  • Adv Sci (Weinh). 2026 Feb;13(12):e10302. doi: 10.1002/advs.202510302.
Chaelin You 1,  Jaewoo Park 1,  Jung Yeon Jang 2,  Junho Noh 1,  Jaehyun Lee 1,  Geunho Kwon 1,  Myeong Sang Yu 2,  Yoo-Sam Chung 2,  Seung-Jun Lee 3,  Keunsoo Kang 4,  Jihwan Park 5,  Ji Heui Kim 2,  Kyuho Kang 1
Affiliations

Affiliations

  • 1 Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Republic of Korea.
  • 2 Department of Otorhinolaryngology-Head and Neck Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 3 Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 4 Department of Microbiology, College of Science & Technology, Dankook University, Cheonan, Republic of Korea.
  • 5 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
PMID: 41498635 DOI: 10.1002/advs.202510302
Abstract

Sinonasal squamous cell carcinoma (SNSCC) is a rare malignancy with poorly understood molecular drivers. Consequently, its cellular composition and tumor microenvironment (TME) remain largely undefined. Here, we performed integrated bulk and single-nucleus multi-omic analyses to map the SNSCC ecosystem. Within the malignant compartment, we identified five distinct populations, with hypoxic (TC1) and proliferative (TC2) subtypes associated with adverse clinical outcomes. Functionally, TC1 cells orchestrate a hypoxia-driven angiogenic program via coordinated secretion of Adrenomedullin (ADM), MIF, and VEGFA, promoting endothelial tip cell (EC1) differentiation. Integrative analysis revealed these transcriptional programs are underpinned by tumor-specific chromatin accessibility and DNA hypomethylation, particularly at AP-1-enriched regulatory elements. Mechanistically, in vitro studies confirmed that this response depends on cooperative AP-1 and HIF1A signaling. Furthermore, histological analysis of patient tissues demonstrated spatial co-localization of GLUT1-expressing TC1 cells with DLL4-positive EC1 cells. These findings elucidate the epigenetic landscape underlying tumor-stromal interactions and establish the ADM/VEGFA axis as a critical therapeutic target to disrupt epigenetically controlled angiogenesis in SNSCC.

Keywords

hypoxia‐angiogenesis axis; multi‐omic profiling; rare cancer genomics; sinonasal squamous cell carcinoma; tumor heterogeneity.

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