Dr. Humam Kadara
The University of Texas MD Anderson Cancer Center
Department of Translational Molecular Pathology
Lung cancer is the leading cause of cancer deaths worldwide. Relative to other tumors found in smokers, lung cancer displays dismal prognosis and its epidemic will remain long after smoking incidence has dropped -- thus warranting new strategies for prevention and early treatment of this fatal disease. Our central goal is to understand how lung cancer, particularly its most frequent subtype lung adenocarcinoma, evolves in smokers and how we can detect and treat this fatal malignancy in its earliest stages. To do so, our laboratory surveys operational genomic, immunogenomic, immune and genome-wide expression programs in “normal” (normal-appearing yet mutagenized) and premalignant phases in lung cancer. To answer these questions, we investigate both human specimens and human-relevant genetically engineered murine models with tobacco carcinogen exposure.
Projects in which trainees would be welcome include:
- 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 adenocarcinoma 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 immunopreventive 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. To so, we are employing single-cell sequencing technology to understand the single-cell landscape of lung adenocarcinoma evolution including premalignancy conversion. 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 adenomatous premalignancy suggesting new venues for personalized prevention. Our current projects continue to focus on characterizing these phenomena at unprecedented resolution at the single-cell level using single-cell sequencing technology.
Rotating and joining graduate students will have the opportunity to interact with a multidisciplinary team of basic scientists, physicians and physician scientists in various fields including cancer biology, carcinogenesis, prevention, oncoimmunology, genomics and immunogenomics. Trainees will also have the opportunity to contribute to multiple projects within the laboratory and in a collaborative setting. In addition, our laboratory provides several opportunities to develop scientific communication and writing skills, including manuscript writing, progress report presentations, poster presentations, and journal club presentations.