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ARTICLE

SNX9 Orchestrates Lung Metastasis via EGFR-ERK Signaling and Actin Cytoskeleton Remodeling in Breast Cancer

Qingqing Liu1,2,#, Lei Li3,4,#, Kumar Ganesan1,2, Yang Jiang5, Kewu Zeng6, Yue Sui1,2, Xinyuan Guan2,7, Rongfang He3,*, Jianping Chen1,2,*
1 School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
2 Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
3 Department of Pathology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
4 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
5 The Department of Traditional Chinese Medicine, Beijing Jishuitan Hospital, Beijing, China
6 School of Pharmaceutical Sciences, Peking University, Beijing, China
7 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
* Corresponding Author: Rongfang He. Email: email; Jianping Chen. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Cancer Metastasis)

Oncology Research https://doi.org/10.32604/or.2026.082536

Received 18 March 2026; Accepted 12 August 2026; Published online 19 August 2026

Abstract

Objectives: Sorting nexin 9 (SNX9) participates in endocytic trafficking and has been connected to several malignancies, but its involvement in breast cancer (BC) remains incompletely resolved. This work was designed to examine whether SNX9 supports BC progression and investigate signaling and cytoskeletal processes associated with its activity. Methods: The clinical relevance of SNX9 was assessed using bioinformatics analysis of publicly available cancer databases. Lentiviral vectors were used to establish BC cell models with stable SNX9 overexpression or knockdown. Both cellular (proliferation and motility) and murine (tumor growth and metastatic colonization) experiments were implemented to functionally characterize the SNX9-mediated phenotypes. The underlying mechanisms were investigated via western blotting, immunofluorescence, co-immunoprecipitation, and pathway-focused analyses. Results: Across the analyzed datasets, greater SNX9 abundance was linked to worse overall survival outcomes in BC patients. Functionally, SNX9 upregulation conferred increased proliferative, migratory, and invasive capacities in vitro and contributed to both primary tumor enlargement and distant metastatic spread in vivo, whereas SNX9 depletion produced the reciprocal phenotypes. SNX9 silencing also increased the G2/M cell fraction and disrupted actin cytoskeletal organization mechanistically linked to reduced Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division cycle 42 homolog (Cdc42) activation and the subsequent impairment of lamellipodial and filopodial protrusion. Additionally, co-immunoprecipitation substantiated the physical coupling between SNX9 and the scaffold protein tyrosine kinase substrate with five SH3 domains (TKS5), which correlated with the invasive behavior of BC cells. Conclusion: Collectively, our findings establish SNX9 as a critical oncoprotein that drives BC progression by coordinating proliferative epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and cytoskeletal dynamics through interactions with TKS5 and Rac1/Cdc42. Clinically, SNX9 qualifies as a promising prognostic classifier and a rational target for therapeutic intervention.

Keywords

Sorting nexin 9 (SNX9); EGFR-ERK signaling; actin cytoskeleton remodeling; breast cancer (BC)

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