Integrative single-cell and bulk RNA sequencing unravels the role of ACTN1 in promoting lung cancer with brain metastasis and epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Overview

1. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
2. The First Clinical School of Anhui University of Traditional Chinese Medicine, Hefei, China
3. Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Abstract

Background: Brain metastasis (BM) remains a severe and fatal complication in patients with lung cancer (LC), presenting a major therapeutic challenge. Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have emerged as a cornerstone of targeted therapy, their clinical efficacy is often limited by the inevitable development of drug resistance.

Methods: We initially constructed a general atlas of the tumor microenvironment (TME) in LCBM lesions by integrating single-cell RNA sequencing (scRNA-seq) data. The sensitivity of each cell cluster to EGFR-TKIs was assessed by the “Beyondcell” method. By performing high-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA), we identified hub genes within an EGFR-TKI resistance-associated cell cluster. Finally, the functional role of the most promising candidate, ACTN1, was further investigated in a constructed osimertinib-resistant LC cell line.

Results: We identified a malignant and therapy-resistant ACTN1+ epithelial cell subcluster. Both signaling and functional enrichment analyses demonstrated marked activation of PI3K-Akt and IL-17 signaling pathways in ACTN1-high patient subgroups. Finally, we applied machine learning methods to the ACTN1-related genes to select prognostic factors. In vitro experiments confirmed the pro-resistance and pro-metastatic functions of ACTN1 in osimertinib-resistant LC cells.

Conclusion: ACTN1 was discovered to induce malignant progression and formation of EGFR-TKI resistance. Targeting ACTN1-related pathways may provide novel insights to treat LCBM and overcome intracranial EGFR-TKI resistance.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE267960 — at NCBI GEO; found in the text, “Data acquisition and preprocessing”

Other data links

• ebi.ac.uk/biostudies/arrayexpress — EMBL-EBI; found in the text, “Data acquisition and preprocessing”
• ncbi.nlm.nih.gov/geo — NCBI; found in the text, “Data acquisition and preprocessing”

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 7 authors, 5 keywords, 112 references.

Cite

This paper

Wu, W., Yang, M., Qin, J., Gui, S., Zhang, Z., Zhang, Y., & Du, Y. (2026). Integrative single-cell and bulk RNA sequencing unravels the role of ACTN1 in promoting lung cancer with brain metastasis and epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Frontiers in cell and developmental biology, 14, 1738641. https://doi.org/10.3389/fcell.2026.1738641

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