SMARCA4 loss promotes late-stage tumor progression in non-neuroendocrine small-cell lung cancer
- Author(s)
- Kirk, NA; Ng, J; Ly, KL; Choi, M; Ban, YH; Dzhivhuho, GA; Jang, J; Ko, KP; Kareta, MS; Park, JL; Karnezis, AN; Thomas, A; Sutherland, KD; Park, KS;
- Journal Title
- Molecular Cancer Research
- Publication Type
- Jan 16
- Abstract
- Role of SMARCA4, a core component of the SWI/SNF chromatin remodeling complex, remains unclear in small-cell lung cancer (SCLC). Using genetically engineered mouse models, we found that Smarca4 deletion markedly reduced tumor formation and decreased expression of ASCL1, a key neuroendocrine lineage factor. However, Smarca4-deficient tumors, though smaller, exhibited aggressive features, including variant histology and loss of neuroendocrine differentiation. In established tumor cells, Smarca4 knockdown did not affect proliferation in vitro but unexpectedly promoted tumor growth in vivo, accompanied by reduced expression and cell-surface display of PVR, a ligand critical for T and NK cell activation. Although the contribution of these immune cells to SMARCA4 tumor-suppressor activity remains unknown, these findings suggest distinct roles of SMARCA4 in promoting early tumor development but restraining progression of late-stage, neuroendocrine-low tumors. Implications: This study underscores the importance of tumor context and timing in understanding and targeting SMARCA4 and other chromatin regulators in SCLC.
- Publisher
- AACR
- Research Division(s)
- ACRF Cancer Biology and Stem Cells
- PubMed ID
- 41489471
- Publisher's Version
- https://doi.org/10.1158/1541-7786.Mcr-25-0592
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-01-29 02:00:43
Last Modified: 2026-01-29 02:01:03