Ann Marie Pendergast

Research Overview:

Tyrosine Kinase-regulated Transcription Networks in tumor progression to metastasis and the regeneration response to injury.

The long-term goal of our research is to define the role of protein tyrosine kinase-regulated transcription networks in the regulation of cell polarity, growth, survival, differentiation, adhesion, and migration during cancer metastasis and the response to tissue injury. We have a long-standing research interest on the role of protein tyrosine phosphorylation in tumorigenesis. Our early research led to seminal discoveries that defined the critical pathways employed by the BCR-ABL tyrosine kinase to induce human leukemia. We employ animal models and state-of-the art transcriptomic technologies to investigate the role of tyrosine kinase-dependent transcription factor networks during tumor metastasis as well as the regeneration response following lung injury. In particular, we are dissecting the pathways that modulate the crosstalk among multiple cell types during metastasis to the brain. Brain metastases represent the most common adult intracranial malignancy with more than 200,000 patients diagnosed in the U.S. annually. Approximately, 20 to 40% of patients with solid tumors will develop brain metastases and lung cancer patients exhibit the highest prevalence of brain metastasis (40-60%) among all cancer types.  Current therapies to treat brain metastases have proven ineffective due to variable, transient and incomplete responses, as well as inability for drugs to cross the blood-brain-barrier (BBB) to reach therapeutic doses to treat brain metastasis. We have recently reported that ABL tyrosine kinase-driven transcriptional networks promote brain metastasis in mouse models, and found that treatment with ABL allosteric inhibitors impairs brain metastasis in pre-clinical models. Among the research areas currently being pursued in our laboratory are defining the mechanisms that regulate the cross-talk between brain metastatic cells and associated cells in the brain tumor microenvironment. High-level expression of ABL1, ABL2 and a subset of ABL-dependent target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature. The ultimate goal of our studies is to develop novel therapies for the treatment of metastatic solid tumors by targeting not only cancer cells but also associated stromal cells in the tumor microenvironment.

Repair following injury requires dynamic intercellular signaling to promote the proper balance of proliferation and differentiation of specialized epithelial progenitor cell populations required to restore normal lung epithelial architecture and barrier function. Absence or imbalance of these processes may result in death or long-term pulmonary disease among survivors. Currently little is known regarding the identity of signaling networks that might be effectively targeted to promote recovery from lung injury. Unexpectedly we found that inhibition of the ABL kinases promotes lung epithelial regeneration in mice after bacterial pneumonia challenge. Further, pathogen exposure elicits a dramatic increase in Abl1 expression in bronchial epithelial cells. Our exciting data demonstrate that inactivation of ABL kinases in mouse models of bacterial and viral pneumonia promotes alveolar epithelial cell regeneration.

Mentoring Philosophy:

My goal is to train the next generation of scientists and leaders by providing essential skills to develop into independent and creative thinkers. I have extensive experience in training and mentoring students, postdoctoral fellows and junior faculty.  My laboratory provides a collegial and highly interactive environment to promote collaboration and engagement among lab members and colleagues across the University. We conduct weekly laboratory research and journal club meetings, and weekly one-on-one meetings with trainees to discuss research progress, trouble shooting, planning future research, and writing publications and grants. Lab trainees have gone to successful academic careers and are currently Professors, Associate and Assistant Professors at various academic institutions. I have also trained outstanding post-doctoral fellows who have gone to successful research careers in industry.