Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

Christopher W Schultz^{1

2

3}, Sourav Saha^{1

4}, Anjali Dhall¹, Yang Zhang¹, Parth Desai⁵, Lorinc S Pongor^{1

6}, David A Scheiblin⁷, Valentin Magidson⁷, Ravi P Shuklah², Robin Sebastian^{1

2

3}, Umeshkumar M Vekariya³, Shahbaz Ahmed², Yilun Sun⁸, Christophe Redon¹, Suresh Kumar¹, Manan Krishnamurthy¹, Henrique B Dias⁹, Vasilisa Aksenova¹⁰, Elizabeth Giordano¹⁰, Nobuyuki Takahashi¹¹, Michael Nirula¹, Mohit Arora¹, Chiori Tabe¹, Maria Sebastian Thomas¹, Rajesh Kumar¹, Yasuhiro Arakawa¹², Ukhyun Jo¹³, Tomasz Skorski³, Beverly A Teicher¹⁴, Roshan Shreshta¹, Mirit I Aladjem¹, Stephen Lockett⁷, Mary Dasso¹⁰, Yves Pommier¹, Ajit K Sharma¹, Anish Thomas¹

Affiliations

¹ Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
² Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
³ Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
⁴ Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
⁵ Department of Hematology & Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.
⁶ Cancer Genomics and Epigenetics Core Group, Hungarian Center of Excellence for Molecular Medicine (HCEMM), Szeged 6728, Hungary.
⁷ Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701.
⁸ Department of Pharmacology, Physiology, and Drug Development, University of Maryland School of Medicine, Baltimore, MD 21201.
⁹ Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
¹⁰ Division of Molecular and Cellular Biology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892.
¹¹ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
¹² Department of Clinical Pharmacology and Therapeutics, Jikei University School of Medicine, Tokyo 105-8461, Japan.
¹³ Developmental Therapeutics Branch and Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
¹⁴ Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD 20892.

PMID: 41129225
PMCID: PMC12582256 (available on 2026-04-23)
DOI: 10.1073/pnas.2503387122

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

Christopher W Schultz et al. Proc Natl Acad Sci U S A. 2025.

. 2025 Oct 28;122(43):e2503387122.

doi: 10.1073/pnas.2503387122. Epub 2025 Oct 23.

Authors

Affiliations

¹ Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
² Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
³ Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
⁴ Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201.
⁵ Department of Hematology & Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.
⁶ Cancer Genomics and Epigenetics Core Group, Hungarian Center of Excellence for Molecular Medicine (HCEMM), Szeged 6728, Hungary.
⁷ Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701.
⁸ Department of Pharmacology, Physiology, and Drug Development, University of Maryland School of Medicine, Baltimore, MD 21201.
⁹ Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
¹⁰ Division of Molecular and Cellular Biology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892.
¹¹ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
¹² Department of Clinical Pharmacology and Therapeutics, Jikei University School of Medicine, Tokyo 105-8461, Japan.
¹³ Developmental Therapeutics Branch and Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
¹⁴ Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD 20892.

PMID: 41129225
PMCID: PMC12582256 (available on 2026-04-23)
DOI: 10.1073/pnas.2503387122

Abstract

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Keywords: R-loops; aging; cancer; replication stress; small-cell lung cancer (SCLC).

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Conflict of interest statement

Competing interests statement:The authors declare no competing interest.

References

1. Xie W., et al. , A-type lamins form distinct filamentous networks with differential nuclear pore complex associations. Curr. Biol. 26, 2651–2658 (2016). - PubMed
1. Dialynas G., et al. , LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle. Hum. Mol. Genet. 21, 1544–1556 (2012). - PMC - PubMed
1. Worman H. J., Bonne G., “Laminopathies”: A wide spectrum of human diseases. Exp. Cell Res. 313, 2121–2133 (2007). - PMC - PubMed
1. Dubik N., Mai S., Lamin A/C: Function in normal and tumor cells. Cancers (Basel) 12, 3688 (2020). - PMC - PubMed
1. Takahashi N., et al. , Replication stress defines distinct molecular subtypes across cancers. Cancer Res. Commun. 2, 503–517 (2022). - PMC - PubMed

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Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

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Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

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