ABSTRACT Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the demands of rapid growth and survival. Within tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) influence tumor metabolism through metabolic crosstalk. However, role of CAF‐derived factors in regulating glutamine metabolism in laryngeal squamous cell carcinoma (LSCC) remains unclear. Primary fibroblasts were isolated from LSCC tumors and adjacent tissues and classified as CAFs or normal fibroblasts (NFs). These were co‑cultured with LSCC cell lines to assess effects on proliferation, migration, invasion, stemness, and chemoresistance using assays such as CCK‑8, EdU, sphere formation, Transwell migration/invasion, and real‑time RTCA assays. Exosomes were harvested from fibroblast‐conditioned media, characterized by TEM, NTA, and Western blotting, and used to treat LSCC cells. Metabolic profiling included Seahorse measurements, TCA metabolites, ATP content, glutamine uptake ( 3 H‐glutamine assay), glutamine consumption, as well as glucose consumption and lactate production assays. Mechanistic studies involved manipulating gene expression via transfection, and detection of targets by qRT‑PCR, Western blotting, and histological staining. Interaction of SFRP2, ELAVL1, and GID8 was assessed via Co‑IP and RIP assays. SFRP2 was increased in LSCC and linked to advanced stage, lymph node metastasis, and poor survival. It was mainly produced by a unique group of CAFs with myofibroblastic traits. Exosomal SFRP2 from these CAFs promoted glutamine uptake, mitochondrial activity, and aggressive tumor behaviors. Mechanistically, SFRP2 stabilized GID8 mRNA via ELAVL1 and promoted β‐catenin nuclear translocation, activating canonical Wnt signaling. A novel CAF‐driven SFRP2–ELAVL1–GID8 pathway promotes metabolic reprogramming involving in LSCC progression.
Pang et al. (Sun,) studied this question.
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