Src/FN1 Pathway Activation Drives Tumor Cell Cluster Formation and Metastasis in Lung Cancer: A Promising Therapeutic Target

Authors

Zujun Que
Zhichao Xi
Dan Qi
Rongchen Dai
Yang Li
Mengfan Liu
Bin Luo
Jiajun Liu
Pan Yu
Yun Yang
Erxi Wu
Hongxi Xu
Jianhui Tian

Language

English

Publication Date

7-11-2025

Journal

Science Advances

DOI

10.1126/sciadv.adv7377

PMID

40632865

PMCID

PMC12239954

PubMedCentral® Posted Date

7-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Lung cancer remains the leading cause of cancer-related death globally, with metastasis driven by circulating tumor cells (CTCs)-particularly clusters-being a major treatment challenge. Despite their critical role, the biological differences between single CTCs and CTC clusters remain unclear. Here, we comprehensively compared their behavioral, transcriptomic, and proteomic profiles in lung cancer models. Compared with single cells, CTC clusters present enhanced metastatic potential, greater survival in the bloodstream and increased resistance to microenvironment. Mechanistically, the Src/FN1 pathway is centrally activated in clusters, promoting intercellular cohesion and protecting against immune clearance and stress in circulation. Pharmacological inhibition of Src with the clinical inhibitor KX2-391 disrupted clustering, impaired CTC survival, and reduced metastasis in preclinical models. Our findings identify the Src/FN1 pathway as a key vulnerability in CTC cluster-driven metastasis, suggesting that Src inhibitors are promising therapeutic strategies to disrupt clustering and improve outcomes in patients with metastatic lung cancer.

Keywords

Lung Neoplasms, Humans, src-Family Kinases, Neoplastic Cells, Circulating, Animals, Signal Transduction, Mice, Neoplasm Metastasis, Cell Line, Tumor, Tumor Microenvironment, Protein Kinase Inhibitors, Proteomics, Gene Expression Regulation, Neoplastic

Published Open-Access

yes

Recommended Citation

Que, Zujun; Xi, Zhichao; Qi, Dan; et al., "Src/FN1 Pathway Activation Drives Tumor Cell Cluster Formation and Metastasis in Lung Cancer: A Promising Therapeutic Target" (2025). Children’s Nutrition Research Center Staff Publications. 299.
https://digitalcommons.library.tmc.edu/staff_pub/299