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Published on: February 28, 2019
Single-Nucleus Multi-Omics Reveals Hypoxia-Driven Angiogenic Programs and Their Epigenetic Control in Sinonasal
Chaelin You1, Jaewoo Park1, Jung Yeon Jang2
1Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Republic of Korea.
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.
Insights
This study reveals subtypes of sinonasal squamous cell carcinoma (SNSCC) linked to poor outcomes. Targeting the adrenomedullin/VEGFA axis offers a new therapeutic strategy for this rare cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Sinonasal squamous cell carcinoma (SNSCC) is rare, with undefined molecular drivers and tumor microenvironment (TME).
- Understanding SNSCC's cellular composition and TME is crucial for developing effective treatments.
Purpose of the Study:
- To comprehensively map the SNSCC ecosystem using integrated multi-omic analyses.
- To identify molecular drivers and therapeutic targets within the SNSCC tumor microenvironment.
Main Methods:
- Integrated bulk and single-nucleus multi-omic analyses (transcriptomics, epigenomics).
- In vitro functional studies and histological analysis of patient tissues.
Main Results:
- Identified five distinct malignant cell populations in SNSCC, including hypoxic (TC1) and proliferative (TC2) subtypes associated with adverse outcomes.
- TC1 cells drive hypoxia-induced angiogenesis via ADM, MIF, and VEGFA secretion, promoting endothelial tip cell (EC1) differentiation.
- Epigenetic alterations, including DNA hypomethylation and chromatin accessibility changes at AP-1 sites, underpin these interactions, dependent on AP-1 and HIF1A signaling.
Conclusions:
- Elucidated the epigenetic landscape governing tumor-stromal interactions in SNSCC.
- Established the ADM/VEGFA axis as a critical therapeutic target to inhibit epigenetically controlled angiogenesis in SNSCC.
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