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Project 1: Mediators of Lung Adenocarcinoma Metastatis

项目1：肺腺癌转移的介质

基本信息

批准号：
10246296
负责人：
JOAN MASSAGUE
金额：
$ 26.31万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246296
关键词：
Antibodies Astrocytes Blocking Antibodies Blood Blood Circulation Blood Vessels Brain CD8-Positive T-Lymphocytes Cancer Patient Cancer Relapse Carcinoma Cell Survival Cells Clinic Clinical Trials Complement Complement 3 Complex Connexin 43 Diagnosis Disease Disease Outbreaks Dissection Distant Early Diagnosis Erlotinib Event Excision Extravasation Future Gap Junctions Genetic Transcription Goals Grant Immune Immune Evasion Immunity Immunologic Surveillance LCN2 gene Lesion Ligands Lung Lung Adenocarcinoma Lymphatic Malignant Neoplasms Malignant neoplasm of lung Meclofenamic Acid Mediating Mediator of activation protein Metastatic Neoplasm to the Central Nervous System Metastatic Neoplasm to the Leptomeninges Metastatic Neoplasm to the Lung Metastatic malignant neoplasm to brain Modeling Molecular Nature Neoplasm Metastasis Neural Cell Adhesion Molecule L1 Operative Surgical Procedures Organ Organoids Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase Preclinical Testing Prevention Prevention approach Primary Neoplasm Regulation Relapse Residual Neoplasm Residual Tumors Residual state Role Seeds Serpins Signal Transduction Stimulator of Interferon Genes TNF gene Therapeutic Time Transforming Growth Factor beta Translating Work base brain parenchyma cancer cell cell motility crizotinib improved inhibitor/antagonist innovation insight lung Carcinoma lung metastatic member mouse model novel strategies pre-clinical preclinical development prevent programs stem stem-like cell targeted treatment therapeutic target

项目摘要

Project 1 (Massagué): Mediators of lung adenocarcinoma metastasis PROJECT SUMMARY Our goal in this project is to elucidate the molecular and cellular determinants of lung adenocarcinoma (adenoCa) metastasis, in order to improve the prevention and treatment of lung cancer relapse. Nearly half of early-diagnosed (stage I and II) lung adenocarcinoma cases develop local and distant relapse despite surgical resection of the primary tumor. Although cancer cell entry into the circulation and extravasation into distant organs are important early steps in the metastatic cascade, the predominant concern in the clinic is about preventing and treating relapse that is driven by cancer cells that were disseminated since before diagnosis. Therefore, our focus is on metastatic colonization, including the phases of metastatic seeding, latency, and outbreak. Building on our previous and new mouse models of brain and multi-organ metastasis, in the current grant period we have identified mediators of metastatic latency and immune evasion by metastatic stem-like cells (MetSCs) (Malladi et al Cell 2016), and mediators of relapse by residual disease after erlotinib and crizotinib treatment of lung adenoCa (Obenauf et al Nature 2015). We also identified serpin mediators of lung MetSC survival in the brain, and defined L1CAM as a mediator of vascular cooption for metastatic outgrowth (Valiente et al Cell 2014). Moreover, we found that carcinoma-astrocyte gap junctions promote brain metastasis by cGAS-STING pathway transfer and pharmacologic modulation of gap junctions is effective against established brain lesions in these models (Chen et al Nature 2016). Our work translated into two clinical trials, one with gap junction modulator meclofenamate and the other anti-TNF antibody certolizumab, in patients with stage IV lung adenoCa. Our future Aim 1 is to define and target the role of L1CAM signaling in lung adenoCa metastasis. We will determine the origin of L1CAM+ lung adenoCa MetSCs, the role of L1CAM signaling in outgrowth, and how to target L1CAM for inhibition of metastasis initiation and propagation. Aim 2 is to elucidate the signaling dynamics and immune evasive state of micrometastatic disease. We will investigate the role of three key pathways –WNT, TGF-β and Hippo– during MetSCs entry and exit from latency, and the role of NK and CD8+ T cells in enforcing latency by NKG2D-mediated recognition of ULBP ligands in MetSCs; the ultimate goal is to trigger immune-mediated clearance of residual disease. Our Aim 3 is to functionally define our recently identified mediators of CNS metastasis as therapeutic targets. We will characterize connexin 43, complement factor 3, and lipocalin 2 as mediators of brain and leptomeningeal metastasis, and will pre-clinically test pharmacologic inhibitors of these targets in combination with therapeutic approaches being developed by other members of this Program Project. Through this work we hope to contribute innovative ideas for the prevention and treatment of lung cancer relapse while retaining our long-term focus on discovering basic principles of metastasis.

项目一（massaguagul）：肺腺癌转移介质