Research
Understanding early mechanisms underlying the pathogenesis of KRAS-mutant lung adenocarcinoma
Our group demonstrated that mice with knockout of the airway lineage gene Gprc5a develop lung adenocarcinomas that are accelerated by tobacco carcinogen exposure. We also demonstrated that lung adenocarcinomas in these mice exhibit high somatic mutation burdens including activating mutations in the KRAS oncogene, the same variants posited to function as drivers of lung adenocarcinomas in human smokers. Our group is employing this human-relevant model to understand the phenotypic evolution of lung adenocarcinomas in vivo including deciphering how smoking-exposed airway cells transition to a lung cancer malignant phenotype.
Interrogating the immune contexture in lung adenocarcinoma pathogenesis
We are discerning crucial roles for the host immune contexture in the phenotypic evolution of KRAS-mutant lung cancer. This includes interrogating the functions of various immunomodulators, including immune checkpoints, during early phases of lung oncogenesis. Additionally, we are probing the potential immunoprevention effects of targeting pro-inflammatory mediators against KRAS-mutant lung cancer.
Exploring uncharted roles of alveolar progenitor cells in development of lung adenocarcinoma
Our laboratory is also interrogating cellular transition states and cells-of-origin of lung adenocarcinoma. Our single-cell sequencing efforts of a rich cohort of epithelial cells from human tissues unraveled novel alveolar intermediate cells (progenitors) that represent likely cells-of-origin for inception of lung adenocarcinoma. To this end, we are using animal models of lung carcinogenesis with reporter genes for tracking specific subsets of alveolar and airway epithelial cells.
Interrogating the role of the host microbiome in the pathogenesis of lung adenocarcinoma
We are using animal models to identify changes to the gut microbiome in response to tobacco-carcinogen exposure and mapping those changes at different stages of premalignancy and tumor development. We are eager to investigate how the microbiome in the gut (and possibly in the lung) evolves during development of lung tumors in the host and how we can leverage these microbial changes for non-invasive early detection of lung malignancy, as well as interrogating potential microbiome-based prevention strategies.
Mapping field cancerization and premalignancy in human lung cancer
Working closely with a team of collaborators, our group has characterized genome-wide DNA and expression alterations in normal-appearing (to the eye) and in preneoplastic lesions preceding early-stage lung cancer in vivo in mice and in human specimens. Additionally, our laboratory has recently defined specific subtypes of lung premalignant lesions suggesting new venues for personalized prevention. Our current projects continue to focus on characterizing these phenomena at unprecedented resolution using single-cell genomics and spatial-omics technologies.
Understanding the malignant conversion of oral precancer
Working with close collaborators in Head and Neck Surgery, we have recently begun exploring mechanisms underlying pathogenesis of oral potentially malignant disorders and their malignant transformation. To this end, we are using novel mouse models for oral carcinogenesis, unique human cohorts of oral precancer and cancer, and innovative spatial technologies.