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Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression
Published on: January 19, 2019
Metastatic organotropism in small cell lung cancer
Manan Krishnamurthy1,2, Anjali Dhall1, Sarthak Sahoo3
1Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
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 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 bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, 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.
Insights
New xenograft models reveal how small-cell lung cancer (SCLC) spreads. Loss of lamin A/C promotes liver metastasis, offering targets for new therapies against this deadly cancer.
Area of Science:
- Oncology
- Cancer Metastasis Research
- Translational Cancer Science
Background:
- Metastasis is the primary cause of cancer mortality, with limited understanding of its regulatory mechanisms.
- Small-cell lung cancer (SCLC) is highly metastatic, but lacks adequate preclinical models for studying metastasis.
- Existing models hinder research into SCLC's aggressive metastatic behavior.
Purpose of the Study:
- To develop novel, clinically relevant preclinical models for studying SCLC metastasis.
- To identify key cellular and molecular mechanisms driving organ-specific metastasis in SCLC.
- To explore therapeutic targets for preventing or treating SCLC metastasis.
Main Methods:
- Development of xenograft models using rapid autopsy-derived SCLC tumors.
- In vivo lineage selection combined with bulk and single-cell multiomic profiling (transcriptomes, chromatin accessibility).
- Analysis of nuclear-cytoskeletal interactions and lamin A/C (LMNA) expression in metastasis.
Main Results:
- Novel xenograft models accurately recapitulate SCLC histopathology and rapid, widespread metastasis.
- Identified critical cellular programs governing metastatic organotropism to liver and brain.
- Loss of lamin A/C increases nuclear deformability and promotes liver metastasis; reduced LMNA expression correlates with poor outcomes in human liver metastases.
Conclusions:
- Introduced effective preclinical models for SCLC metastasis research.
- Highlighted the crucial role of nuclear-cytoskeletal interactions, specifically LMNA, in SCLC liver metastasis.
- Findings offer new therapeutic strategies targeting organ-specific metastatic pathways in SCLC.
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