Work

Multi‐omics and Functional Analyses Identify Cancer‐associated Fibroblast‐derived Insulin‐like Growth Factor 1 as a Stromal Mediator of Lung Adenocarcinoma Progression

Year: 2026

Type: article

Abstract: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, yet the stromal mechanisms driving rapid disease progression are incompletely understood. Here, we integrated single-cell RNA sequencing with exploratory whole-exome sequencing to characterize tumor microenvironment remodeling in a rapidly progressing LUAD patient. Tumor tissue exhibited marked stromal enrichment, with inflammatory cancer-associated fibroblasts (CAFs) constituting a prominent fibroblast subset. Receptor-ligand and cell-type-specific expression analyses identified CAF-derived insulin-like growth factor 1 (IGF1) as a potential stromal mediator of LUAD progression. This fibroblast-specific IGF1 pattern was corroborated by an external single-cell dataset and by immunofluorescence validation in LUAD tissues with or without bone metastasis. Functionally, recombinant IGF1 enhanced LUAD cell proliferation, migration, and invasion, whereas IGF1 knockdown in CAF-like cells attenuated these malignant phenotypes in co-culture models. In vivo, IGF1 knockdown in CAF-like cells reduced distant metastatic burden, accompanied by alterations in Wnt-related signaling, extracellular matrix organization, and metastasis-associated molecules. These findings indicate that CAF-derived IGF1 contributes to LUAD progression and bone metastatic remodeling through paracrine stromal-tumor communication, highlighting the IGF1/IGF1R axis as a potential stromal-directed therapeutic target in selected LUAD patients.

Source: MedComm

DOI: 10.1002/mco2.71123