SREBP1-mediated lipid metabolism reprogramming drives malignant progression and therapeutic resistance in HPSCC organoids and animal models

Abstract

Head and neck squamous cell carcinoma (HNSCC) presents significant therapeutic challenges owing to its elevated recurrence rate and resistance to chemotherapeutic interventions. Tumor organoid models serve as essential platforms for investigating tumor physiology and pathological functions in vivo for its similarities in recapitulating the spatial structure of HNSCC. We employed HPSCC organoids from typical cell line and patient tissues, which faithfully recapitulated the tumor architecture, combined with CRISPR/Cas9 screening and TCGA-HNSCC database analysis. We identified SREBP1, a master regulator of lipid metabolism, as a key molecule whose expression escalates during HNSCC progression and correlates with improved patient survival and chemotherapy response. Functional studies demonstrated that SREBP1 downregulation conferred resistance to cisplatin and reduced cell death in both organoid and xenograft models in human hypopharyngeal carcinoma (HPSCC). We also found that the downregulation of SREBP1 was associated with enhanced resistance to cisplatin and a reduction in cell death in HPSCC-organoid models ex vivo and xenograft mouse models in vivo. Our findings establish SREBP1-mediated lipid rewiring as a critical determinant of HNSCC pathogenesis and treatment outcomes. Consequently, our model offers a promising solution for the swift and accurate evaluation of chemotherapy efficacy and identifies SREBP1 as a potential therapeutic target in HPSCC.