Abstract 5127: Metastatic organotropism in small cell lung cancer

Abstract Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized well-annotated rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive transcriptomic, epigenomic, and single cell multi-omic analyses, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease. Citation Format: Manan Krishnamurthy, Anjali Dhall, Christopher W. Schultz, Michelle Baird, Parth A. Desai, Jacob Odell, Sarthak Sahoo, Nobu Takahashi, Michael Nirula, Sophie Zhuang, Yue Huang, Brett Schroeder, Yang Zhang, Christophe Redon, Christina Robinson, Lai Thang, Lilia Ileva, Nimit L. Patel, Joseph D. Kalen, Alice-Anaïs Varlet, Noam Zuela-Sopilniak, Ankita Jha, Darawalee W. Zong, Donna Butcher, Tamara Morgan, Alyah Afzal, Raj Chari, Karim Baktiar, Suresh Kumar, Lorinc Pongor, Simone Difilippantonio, Mirit I. Aladjem, Yves Pommier, Mohit K. Jolly, Jan Lammerding, Ajit K. Sharma, Anish Thomas. Metastatic organotropism in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5127.