
The long-term goal of our research is to define the pathways that integrate activation of growth factor, chemokine and adhesion receptors to the regulation of morphogenesis, cell polarity, growth, differentiation, adhesion, and migration during cancer and in response to injury. We have a long-standing research interest on the role of protein tyrosine phosphorylation in tumorigenesis and inflammation. Our early research led to seminal discoveries that defined the critical pathways employed by the Bcr-Abl tyrosine kinase to induce human leukemias. Currently, we are employing novel animal models to investigate the role of tyrosine kinase signaling networks in the regulation of cell polarity, growth, differentiation, adhesion and migration required for tumor progression and inflammatory responses. In particular, we are dissecting the pathways that modulate the crosstalk between multiple cell types during tumor progression and metastasis. Disrupting these “intercellular conversations” is expected to generate new targets for therapeutic intervention. Specifically, we focus on the role of the Abl family of tyrosine kinases, Abl1 and Abl2 (Arg), and associated actin regulatory proteins in diverse cellular processes leading to changes in cell morphology, motility, invasion, adhesion, as well as cell growth and survival. Among the research areas currently being pursued in our laboratory are defining the mechanisms that regulate the cross-talk between cancer cells and associated cells in the tumor microenvironment. We have recently uncovered a previously unknown role for Abl kinases in the regulation of tumor-bone interactions by breast cancer cells and showed that Abl kinases promote breast cancer osteolytic metastasis by activating transcriptional networks dependent on TAZ and STAT5. Moreover, we found that ABL kinases promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses lung cancer cell metastasis and ABL kinases are required for expression of pro-metastasis genes in lung cancer cells. ABL-mediated activation of the TAZ and b-catenin transcriptional co-activators is required for lung adenocarcinoma metastasis, and ABL kinases activate TAZ- and b-catenin by decreasing their interaction with the b-TrCP ubiquitin ligase leading to increased protein stability. High-level expression of ABL1, ABL2 and a subset of ABL-dependent TAZ- and b-catenin-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.
Education and Training
- University of California - Riverside, Ph.D. 1986
Selected Grants and Awards
- Pharmacological Sciences Training Grant
- NINDS Research Education Programs for Residents and Fellows in Neurosurgery
- Viral Oncology Training Grant
- Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
- Duke Resident Physician-Scientist Program in Radiation Oncology and Radiology
- ABL kinases promote lung cancer brain metastasis through regulation of transcriptional networks
- Medical Scientist Training Program
- Training Program in Developmental and Stem Cell Biology
- Exploring the role of polyploidy in tumor progression
- Unraveling the Role of ABL 1 and 2 Drivers of Medulloblastoma Leptomeningeal Metastases
- Identification of actionable networks promoting breast cancer progression and brain metastasis
- Translational Research in Surgical Oncology
- The Role of Abl Kinase Signaling in HER2+ Breast Cancer Brain Metastasis
- Organization and Function of Cellular Structure
- Pharmacological Sciences Training Program
- Uncovering actionable signaling pathways required for solid tumor brain metastasis
- Novel target for therapy refractory lung tumors
- Pharmacology Industry Internships for Ph.D. Students
- Investigation of an ABL kinase-dependent signaling axis required for lung cancer brain metastasis
- Role of ErbB Receptor Signaling in Regulating Normal and Leukemic Stem Cell Fate
- Thermo Lumos Tribrid High-Resolution Accurate-Mass Tandem Mass Spectrometer
- ABL kinase inhibition in mouse models of metastatic and therapy-resistant lung cancer
- Regulation of cell permeability by Abl kinases and implications for the treating of acute lung injury
- Targeting Integrator Kinases in Lung Cancer Metastasis
- Designing durable apoptosis-targeting therapies for acute myeloid leukemia
- Role of Abl Kinases in immune cell signaling
- Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
- Cancer Biology Training Grant
- Identification of a novel target for treating breast cancer metastasis
- Novel druggable pathway required for lung cancer progression and metastasis
- Molecular Basis of Signaling by the cAbl Proto-Oncogene
- Intercellular adhesion and morphogenesis: role of actin-regulatory proteins
- Integrated instrument systems for maintenance and delivery of RNAi libraries
- Signal Amplification by an RTK/Abl Kinase Module
- Biomarker Studies for Novel Anti-Cancer Agents
- Role of Tyrosine Kinases & Adaptor Proteins in Migration
- Erythropoietin Receptor Regulation of Erythorpoiesis
- Same
- Adaptor Proteins And Malignant Transformation
- Same
- Bcr/Abl Signaling In Human Leukemias
- Analysis Of Bcr/Abl Signaling In Human Leukemias
- Molecular Basis Of Signaling By The Cab1 Proto-Oncogene
- Molecular Basis Of Signaling By The Cabl Proto-Oncogene