Ann Pendergast

Overview:

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.

 

Positions:

Anthony R. Means Cancer Biology Distinguished Professor

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1986

University of California - Riverside

Grants:

Exploring the role of polyploidy in tumor progression

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Erythropoietin Receptor Regulation of Erythorpoiesis

Administered By
Medicine, Hematology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Role of ErbB Receptor Signaling in Regulating Normal and Leukemic Stem Cell Fate

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Investigation of an ABL kinase-dependent signaling axis required for lung cancer brain metastasis

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The Role of Abl Kinase Signaling in HER2+ Breast Cancer Brain Metastasis

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.

Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.
Authors
Luttman, JH; Hoj, JP; Lin, KH; Lin, J; Gu, JJ; Rouse, C; Nichols, AG; MacIver, NJ; Wood, KC; Pendergast, AM
MLA Citation
Luttman, Jillian Hattaway, et al. “ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.Cell Rep, vol. 37, no. 4, Oct. 2021, p. 109880. Pubmed, doi:10.1016/j.celrep.2021.109880.
URI
https://scholars.duke.edu/individual/pub1500503
PMID
34706244
Source
pubmed
Published In
Cell Reports
Volume
37
Published Date
Start Page
109880
DOI
10.1016/j.celrep.2021.109880

Role of the ABL tyrosine kinases in the epithelial-mesenchymal transition and the metastatic cascade.

The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease. Video abstract.
Authors
Luttman, JH; Colemon, A; Mayro, B; Pendergast, AM
MLA Citation
Luttman, Jillian Hattaway, et al. “Role of the ABL tyrosine kinases in the epithelial-mesenchymal transition and the metastatic cascade.Cell Commun Signal, vol. 19, no. 1, May 2021, p. 59. Pubmed, doi:10.1186/s12964-021-00739-6.
URI
https://scholars.duke.edu/individual/pub1483299
PMID
34022881
Source
pubmed
Published In
Cell Communication and Signaling : Ccs
Volume
19
Published Date
Start Page
59
DOI
10.1186/s12964-021-00739-6

The ABL2 kinase regulates an HSF1-dependent transcriptional program required for lung adenocarcinoma brain metastasis.

Brain metastases are the most common intracranial tumors in adults and are associated with increased patient morbidity and mortality. Limited therapeutic options are currently available for the treatment of brain metastasis. Here, we report on the discovery of an actionable signaling pathway utilized by metastatic tumor cells whereby the transcriptional regulator Heat Shock Factor 1 (HSF1) drives a transcriptional program, divergent from its canonical role as the master regulator of the heat shock response, leading to enhanced expression of a subset of E2F transcription factor family gene targets. We find that HSF1 is required for survival and outgrowth by metastatic lung cancer cells in the brain parenchyma. Further, we identify the ABL2 tyrosine kinase as an upstream regulator of HSF1 protein expression and show that the Src-homology 3 (SH3) domain of ABL2 directly interacts with HSF1 protein at a noncanonical, proline-independent SH3 interaction motif. Pharmacologic inhibition of the ABL2 kinase using small molecule allosteric inhibitors, but not ATP-competitive inhibitors, disrupts this interaction. Importantly, knockdown as well as pharmacologic inhibition of ABL2 using allosteric inhibitors impairs expression of HSF1 protein and HSF1-E2F transcriptional gene targets. Collectively, these findings reveal a targetable ABL2-HSF1-E2F signaling pathway required for survival by brain-metastatic tumor cells.
Authors
Hoj, JP; Mayro, B; Pendergast, AM
MLA Citation
Hoj, Jacob P., et al. “The ABL2 kinase regulates an HSF1-dependent transcriptional program required for lung adenocarcinoma brain metastasis.Proc Natl Acad Sci U S A, vol. 117, no. 52, Dec. 2020, pp. 33486–95. Pubmed, doi:10.1073/pnas.2007991117.
URI
https://scholars.duke.edu/individual/pub1468820
PMID
33318173
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
117
Published Date
Start Page
33486
End Page
33495
DOI
10.1073/pnas.2007991117

Mesenchymal stem cells promote metastasis through activation of an ABL-MMP9 signaling axis in lung cancer cells.

Mesenchymal stem cells (MSCs) are recruited and activated by solid tumors and play a role in tumor progression and metastasis. Here we show that MSCs promote metastasis in a panel of non-small cell lung cancer (NSCLC) cells. MSCs elicit transcriptional alterations in lung cancer cells leading to increased expression of factors implicated in the epithelial-to-mesenchymal transition (EMT) and secreted proteins including matrix metalloproteinase-9 (MMP9). MSCs enhance secretion of enzymatically active MMP9 in a panel of lung adenocarcinoma cells. High expression of MMP9 is linked to low survival rates in lung adenocarcinoma patients. Notably, we found that ABL tyrosine kinases are activated in MSC-primed lung cancer cells and functional ABL kinases are required for MSC-induced MMP9 expression, secretion and proteolytic activity. Importantly, ABL kinases are required for MSC-induced NSCLC metastasis. These data reveal an actionable target for inhibiting MSC-induced metastatic activity of lung adenocarcinoma cells through disruption of an ABL kinase-MMP9 signaling axis activated in MSC-primed lung cancer cells.
Authors
Gu, JJ; Hoj, J; Rouse, C; Pendergast, AM
MLA Citation
Gu, Jing Jin, et al. “Mesenchymal stem cells promote metastasis through activation of an ABL-MMP9 signaling axis in lung cancer cells.Plos One, vol. 15, no. 10, 2020, p. e0241423. Pubmed, doi:10.1371/journal.pone.0241423.
URI
https://scholars.duke.edu/individual/pub1464400
PMID
33119681
Source
pubmed
Published In
Plos One
Volume
15
Published Date
Start Page
e0241423
DOI
10.1371/journal.pone.0241423

Salting the Soil: Targeting the Microenvironment of Brain Metastases.

Paget's "seed and soil" hypothesis of metastatic spread has acted as a foundation of the field for over a century, with continued evolution as mechanisms of the process have been elucidated. The central nervous system (CNS) presents a unique soil through this lens, relatively isolated from peripheral circulation and immune surveillance with distinct cellular and structural composition. Research in primary and metastatic brain tumors has demonstrated that this tumor microenvironment (TME) plays an essential role in the growth of CNS tumors. In each case, the cancerous cells develop complex and bidirectional relationships that reorganize the local TME and reprogram the CNS cells, including endothelial cells, pericytes, astrocytes, microglia, infiltrating monocytes, and lymphocytes. These interactions create a structurally and immunologically permissive TME with malignant processes promoting positive feedback loops and systemic consequences. Strategies to interrupt interactions with the native CNS components, on "salting the soil," to create an inhospitable environment are promising in the preclinical setting. This review aims to examine the general and specific pathways thus far investigated in brain metastases and related work in glioma to identify targetable mechanisms that may have general application across the spectrum of intracranial tumors.
Authors
MLA Citation
Srinivasan, Ethan S., et al. “Salting the Soil: Targeting the Microenvironment of Brain Metastases.Mol Cancer Ther, vol. 20, no. 3, Mar. 2021, pp. 455–66. Pubmed, doi:10.1158/1535-7163.MCT-20-0579.
URI
https://scholars.duke.edu/individual/pub1471070
PMID
33402399
Source
pubmed
Published In
Mol Cancer Ther
Volume
20
Published Date
Start Page
455
End Page
466
DOI
10.1158/1535-7163.MCT-20-0579