Member Biography

Past research 1. Defective polarity as a precursor to lung premalignancy. Cell polarity is an essential regulator of the cytoskeleton, organizing cellular architecture and tissue level mechanics and further controls numerous cellular signaling pathways within homeostatic epithelia1. Changes in cellular architecture are a feature of the various stages of tumor progression. I demonstrated that the apical polarity Crumbs3 (CRB3) plays a vital role in the luminal cells of the pseudostratified adult airway epithelia. By depleting CRB3 in various luminal cell types, I demonstrated that activation of YAP and TAZ, which are transcriptional effectors of the Hippo signaling pathway, drive cell fate plasticity and resulting the secretion of various pro-proliferation ligands, including several ERBB family ligands, resulting in squamous lesions. Genetic deletion of YAP/TAZ or pharmacological inhibition of ERBB receptors prevents and treats precancer airway lesion development. Our analyses further demonstrated that YAP and TAZ drive a unique transcriptional program that involves the TEAD and TP63 family of transcription factors in basal cells expanding in precancer bronchial lesions, which include the repression of immune modulating factors that contributes to immune evasion during progression to lung squamous cell carcinoma. The study sheds light on the mechanisms underlying the development of precancerous lesions and provides new insights into potential therapeutic targets for lung cancer prevention. 2. YAP/TAZ control cytoskeletal dynamics to maintain PCP, airway motile cilia, and mucociliary clearance. The mucociliary escalator transports foreign debris from the depths of our lungs along the airways by the coordinated beating of apical motile cilia of specialized cells. As part of this study, I observed an interesting apical localization pattern for YAP in multiciliated cells in the airway, with phosphorylated YAP (pS127, a site modified by Hippo pathway kinases) exhibiting a planar polarized localization pattern about basal bodies, and at the proximal edges of multiciliated cells, suggesting a role for YAP/TAZ in planar cell polarity in multiciliated cells. We found that the conditional loss of YAP/TAZ in adult multiciliated cells (using Foxj1-CreRT2) resulted in the loss of axonemal structures of motile cilia and severe ciliary beating defects. Future research Investigate the role of synergistic signaling pathways that promote lung premalignancy. Preliminary observations and rationale: Lung cancer remains the leading cause of cancer mortality worldwide primarily due to our inability to detect the disease at its earliest stage and lack of interventions to prevent its development in those at highest risk. The rate-limiting step is our lack of understanding of the earliest molecular and cellular changes associated with lung carcinogenesis. Using chemical and genetic modulation of the Notch and Hippo pathways, I will investigate the early events that induce the transition of naturally occurring squamous epithelium in the airways (defined as Hillock cells) into malignant lung cancer. I have previously demonstrated that defective cell polarity gives rise to the amplification of squamous lesions that arise from airway basal stem cells. Using lineage tracing and transgenic mouse models, I will investigate the function of these squamous lesions during the regeneration process and determine their role in initiating lung cancer. 3.1. Understanding the functions of Hillocks. Hillock cells are highly proliferative cells found in distinct regions of the trachea, which express markers associated with squamous epithelial differentiation, cellular adhesion, and immunomodulation. The trajectory of cells that arise from hillocks are currently unknown, and therefore I will map out the fate of hillock cells by combining airway injuries and lineage tracing. This will provide an essential understanding of how these cells contribute to the regeneration of the tracheal epithelium. The frequency of hillock cells in the airway increases with age, which raises questions about whether these cells can be considered age-associated adult stem cells of the trachea, as the conventional basal cells show a decline in their proliferative capabilities. 3.2. Premalignancy of squamous lesions in the trachea. Squamous lesions are thought to be the precursors of aggressive squamous carcinoma of the lung. Using lineage tracing coupled with 1) genetic manipulation of established tumor suppressor genes and 2) chemical carcinogens I will study the role of hillock cells and their contributions to lung carcinogenesis. These hillock cells of the airway likely hold traits that facilitate the transition toward malignancy due to their inherent proliferative capacity and squamous identity.

Ph.D. - University of St. Andrew, Fife 09/2016

Post-doctoral Fellowship - Boston University, Boston, MA 05/2024