Hypoxia‐induced secretory autophagy in cancer‐associated fibroblasts promotes ECM remodelling through serglycin secretion in oral squamous cell carcinoma

作者：Yan Zhang, Tao Cheng, Xiteng Yin, Zhi Wang, Yuyang Zhang, J. Yu, Yufeng Wang, Wei Han · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70556 · 被引用次数：3 · 研究领域：Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease、Cancer, Hypoxia, and Metabolism

BACKGROUND: The worst pattern of invasion (WPOI) is a critical histological prognostic indicator in oral squamous cell carcinoma (OSCC), yet the underlying mechanisms driving high WPOI remain poorly understood. While cancer-associated fibroblasts (CAFs) and their secreted factor serglycin (SRGN) are implicated in tumour progression, the regulation of SRGN secretion within the hypoxic tumour microenvironment is unknown. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on 6 OSCC samples (3 each of WPOI 1-3 and 4-5) to identify subgroups of CAFs and their characteristic gene expression profiles. Using Western blot, qRT-PCR, and immunofluorescence, we investigated hypoxia-induced SRGN secretion pathways. Complementary CRISPR-Cas9 knockout, Co-IP assays, and xenograft models elucidated SRGN's role in ECM remodelling. RESULTS: ScRNA-seq revealed significant enrichment of CAFs, particularly an SRGN-expressing myCAF subpopulation, in high-WPOI (4-5) OSCC tissues. Under hypoxia, CAFs switched SRGN secretion from the conventional ER-Golgi pathway to an unconventional secretory autophagy pathway, dependent on autophagosome formation but independent of lysosomal degradation. Secreted SRGN directly interacted with matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) in the extracellular matrix (ECM), enhancing ECM remodelling and OSCC invasion and migration. In vivo, either genetic ablation of SRGN in CAFs or pharmacological inhibition of autophagy significa...