EXPLORING THE LINK BETWEEN LUNG CANCER LINEAGE HETEROGENEITY AND MICROENVIRONMENT

Personnel: I am an Assistant Professor in the Division of Pulmonary, Critical Care, and Sleep Medicine in the Icahn School of Medicine at Mount Sinai. Since the completion of my clinical training, my research career has been entirely dedicated to the studies of lung cancer. As a postdoc, I spearheaded efforts to elucidate the roles of lineage factors amplified in lung cancer and have pioneered the field of lineage regulations in lung cancer while establishing my expertise in genomic analyses and chromatin biology. My mentor, Dr. Powell, is Chair of the Division, and his research has centered on identifying biomarkers that can distinguish invasive from non-invasive lung cancers through genomic approaches. He has been continuously funded by NCI/NIH (R01CA163772, R01CA120174), awarded an ACS Research Scholar Grant, and funded by private foundations, all of which focus on the study of lung cancer. He is the founding Chair of the Thoracic Oncology Section of ATS, where he played an integral role in establishing 2015 WHO classification of lung tumors. Career Development: As the only basic research group solely dedicated to studying lung cancer in Mount Sinai, I am committed to understanding lung cancer as a disease of lung differentiation program, a critical component of tissue maintenance under-recognized in solid tumor biology, and thoroughly disentangling the complexity of their lineage programs, with a goal to advance it into a tractable path for clinical utility. This award would support a study validating the biological significance of our large-scale epigenomic analyses and supporting the novel ideas that tumor lineages contribute to differential interaction between the tumor and tumor microenvironment, with a hope to develop a new strategy to chemically modulate lineage programs, as well as provide me with an opportunity to hone my skills to develop genomic technologies and necessary partnerships to complement them. The platform and a novel technique to profile single-cell enhancers will enable us to analyze the heterogeneity of lung cancers and to elucidate their reprogramming plasticity to overcome selective survival pressures or adapt to its microenvironment.Research (Background): Lung cancers manifest with dramatic heterogeneity; however, it is unclear how that contributes to carcinogenesis and therapeutic response. Increasing evidence supports that the tumor microenvironment plays essential roles in tumor initiation and progress; immune cell infiltrates are heterogeneous; and the structure of stromal cells can dictate the ability of the immune system to engage. We previously uncovered the roles of lineage-amplified oncogenes in lung cancer, and yet the relationship between malignant cells and their molecular regulators remains poorly understood. Different cell types of the lung respond to various microenvironmental signals differently, and it is plausible that tumor cells retain such characteristics. While there has been rapid progress in understanding the tumor microenvironment and its relevance to immunotherapy, their interactions with cancer cells remain elusive. Area of Emphasis: The study seeks to uncover relationships between the lineage states of the lung tumors and microenvironmental features and seeks to elucidate molecular mechanisms influencing those interplays, in alignment with the LCRP’s rea of emphasis to “understand the molecular mechanisms of initiation and progression to clinically significant lung cancer.”Objective/Hypothesis: We will leverage our expertise on epigenome technologies and the expertise at Mount Sinai on immunology to identify potential relationships between immune responses/stromal architectures and lung cancer lineage states. Specific Aims and Study Design: First, we will use archived specimens to infer their lineage from chromatin profiles and find correlations with microenvironmental characteristics. Secondly, we will further profile epithelial components of freshly resected tumors simultaneously profiled for microenvironmental genomic features at the single cell level to identify specific molecular features of the tumor microenvironment related to a tumor state. Finally, to capture and to establish a model on lineage diversity in lung cancers, we will further utilize our preclinical models to evaluate populational diversity and shift in their relationship to their microenvironment. Impact: It will provide novel insights into what lineage programs are involved in the process of forming tumor microenvironment, which leads to further studies on the roles of lineage programs. The interaction at the molecular level between lung cancer cells and surrounding cells may be therapeutically exploited by chemical intervention. Military Relevance: Military personnel are at higher risk of exposure to unique carcinogens that may lead to representing distinct subclasses of lung cancers and a unique microenvironment. Proper molecular classification of subtypes in relationship with its surroundings allows us to improve upon existing therapeutic options. Thus, this study will have great impacts on the bettering of health for military members.