Ann Pendergast

Overview:

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.

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 at 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

Identification of actionable networks promoting breast cancer progression and brain metastasis

Administered By
Pharmacology & Cancer Biology
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Identification of a novel target for treating breast cancer metastasis

Administered By
Pharmacology & Cancer Biology
Role
Principal Investigator
Start Date
End Date

Publications:

A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis.

Brain metastases are a common consequence of advanced lung cancer, resulting in cranial neuropathies and increased mortality. Currently, there are no effective therapies to treat brain metastases due to a lack of actionable targets and a failure of systemic therapies to penetrate the blood-brain barrier (BBB). Here we identify an autocrine signaling axis required for lung adenocarcinoma brain metastasis, whereby nuclear accumulation of the TAZ transcriptional co-activator drives expression of a panel of transcripts enriched in brain metastases, including ABL2 and AXL, encoding for protein tyrosine kinases that engage in bidirectional signaling. Activation of ABL2 in turn promotes TAZ tyrosine phosphorylation and nuclear localization, establishing an autocrine AXL-ABL2-TAZ feed-forward signaling loop required for brain metastasis colonization. Notably, treatment with a BBB-penetrant ABL allosteric inhibitor or knockdown of ABL2, AXL, or TAZ markedly decreases brain metastases. These findings suggest that ABL and AXL inhibitors might be effective against brain metastases.
Authors
Hoj, JP; Mayro, B; Pendergast, AM
MLA Citation
Hoj, Jacob P., et al. “A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis..” Cell Rep, vol. 29, no. 11, Dec. 2019, pp. 3421-3434.e8. Pubmed, doi:10.1016/j.celrep.2019.11.018.
URI
https://scholars.duke.edu/individual/pub1423612
PMID
31825826
Source
pubmed
Published In
Cell Reports
Volume
29
Published Date
Start Page
3421
End Page
3434.e8
DOI
10.1016/j.celrep.2019.11.018

Correction: ABL kinase inhibition sensitizes primary lung adenocarcinomas to chemotherapy by promoting tumor cell differentiation (Oncotarget (2019) 10 (1874-1886) DOI: 10.18632/oncotarget.26740)

© 2019 Impact Journals LLC. All rights reserved. This article has been corrected: In Figure 2D, the panel for the loading control should be labeled 'tubulin', not 'GAPD.' We have corrected the legend to Figure 2D by updating this sentence: "Phospho-CrkL is a marker for Abl kinase activity while a-tubulin is a loading control." In addition, we have added a sentence to the legend of Figure 5C to clarify the origin of the lysates: "C) Western blot (using the same lysates as Figure 2D) analysis showed no significant difference in total Yap1 protein expression in double treated mice compared to vehicle treated control mice." The corrected Figure 2D and the corrected legend of Figure 5 are shown below. The authors declare that these corrections do not change the results or conclusions of this paper.
Authors
Khatri, A; Gu, JJ; McKernan, CM; Xu, X; Pendergast, AM
URI
https://scholars.duke.edu/individual/pub1417927
Source
scopus
Published In
Oncotarget
Volume
10
Published Date
Start Page
6045
End Page
6046

BCR-ABL-INDUCED ONCOGENESIS IS MEDIATED BY DIRECT INTERACTION WITH THE SH2 DOMAIN OF THE GRB-2 ADAPTER PROTEIN

Authors
GISHIZKY, ML; QUILLIAM, LA; CRIPE, LD; BASSING, CH; DAI, ZH; LI, NX; BATZER, A; RABUN, KM; DER, CJ; SCHLESSINGER, J; PENDERGAST, AM
MLA Citation
GISHIZKY, M. L., et al. “BCR-ABL-INDUCED ONCOGENESIS IS MEDIATED BY DIRECT INTERACTION WITH THE SH2 DOMAIN OF THE GRB-2 ADAPTER PROTEIN.” Journal of Cellular Biochemistry, WILEY-LISS, 1994, pp. 116–116.
URI
https://scholars.duke.edu/individual/pub904761
Source
wos
Published In
Journal of Cellular Biochemistry
Published Date
Start Page
116
End Page
116

Targets of the ABL tyrosine kinases in normal and transformed cells.

Authors
MLA Citation
Pendergast, A. M. “Targets of the ABL tyrosine kinases in normal and transformed cells..” British Journal of Cancer, vol. 78, CHURCHILL LIVINGSTONE, 1998, pp. 2–2.
URI
https://scholars.duke.edu/individual/pub904755
Source
wos
Published In
British Journal of Cancer
Volume
78
Published Date
Start Page
2
End Page
2

Role of the Abl tyrosine kinases and their targets in the regulation of the dynamic cytoskeleton

Authors
MLA Citation
Pendergast, A. M. “Role of the Abl tyrosine kinases and their targets in the regulation of the dynamic cytoskeleton.” Faseb Journal, vol. 15, no. 4, FEDERATION AMER SOC EXP BIOL, 2001, pp. A505–A505.
URI
https://scholars.duke.edu/individual/pub904763
Source
wos
Published In
Faseb Journal
Volume
15
Published Date
Start Page
A505
End Page
A505