Research Faculty

Address
1130 St. Nicholas Street
ICRC Room 217A
New York, NY 10032


Phone: 212-851-4731
Fax:

cabateshen@columbia.edu
Education and Training
Fordham University (BA)
Cornell University Medical School (Ph.D.)


Collaborations
Collaborations with: Michael Shen (CUMC), Andrea Califano (CUMC), Mitchell Benson (CUMC), Victor Reuter (MSKCC), Robert Cardiff (UC Davis)
Multi-investigator grant participation with: Mark Rubin (Weil Cornell), Charles Sawyers (MSKCC)

Affiliations
Herbert Irving Comprehensive
Cancer Center

Stem Cell Consortium


Training Activities
Cancer Biology class – provided one lecture
Supervise Intell Student project
Cory Abate-Shen, Ph.D
Professor of Urology and Pathology
Director of Research, Department of Urology
Associate Director, Herbert Irving Comprehensive Cancer Center
Research Summary

The Abate-Shen laboratory has a long-standing interest in understanding the relationship between the processes that control normal development and those that lead to cancer, which has been focused on analyses of vertebrate homeobox genes. In particular, the laboratory has taken a multi-disciplinary approach to investigate how homeobox genes regulate gene transcription during development, as well as how their aberrant expression contributes to tumorigenesis. This work has led to the generation of new mouse models of human cancer, which have provided important insights regarding mechanisms of tumorigenesis, as well as pre-clinical models for chemoprevention and chemotherapy.

A major focus of the Abate-Shen laboratory has been the development of novel mouse models for prostate cancer, which recapitulate all stages of the disease. They have used models of early stage prostate cancer to understand how the disease is initiated and have also performed pre-clinical studies, which have uncovered novel mechanisms for cancer prevention. In addition, the laboratory has developed mouse models of advanced prostate cancer and have used these to investigate the pathways by which these lethal forms of prostate cancer arise and to investigate how to target these pathways for cancer treatment. Recently, the Abate-Shen laboratory has developed new mouse models of invasive bladder cancer and are using these models to understand how this deadly disease arises and to develop new therapeutic treatments.

The Abate-Shen Lab

Service Activities

American Association for Cancer Research – various committee activities
NCI – Site Review Committee

Selected Publications

Wang, J., Kumar, R., Biggs, V.J., Lee, H., Chen, Y., Kagey, M.H., Young, R.A., and Abate-Shen, C. (2011) The Msx1 homeoprotein recruits Polycomb to the nuclear periphery during development. Dev. Cell 21:575-588.

Wang, J. and Abate-Shen, C. (2012). The Msx1 Homeoprotein recruits G9a methyltransferase to repressed target genes in myoblast cells. PLoS ONE 7:e37647.

Floc’h, N., Kinkade, C., Kobayashi, T., Aytes, A., Lefebvre, C., Mitrofanova, A., Cardiff, R., Califano, A., Shen, M. and Abate-Shen, C. (2012) Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Research 72: 4483-93

Wang, J., Kobayashi, T., Floc’h, N., Kinkade, C., Aytes, A., Dankort, D., Lefebvre, C., Mitrofanova, A., Cardiff, R., McMahon, M., Califano, A., Shen, M. and Abate-Shen, C. (2012) B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. Cancer Research 72: 4765-4776

Wang, Z. A., Mitrofanova, A., Bergren, S. K., Cardiff, R. D., Abate-Shen, C., Califano, A., and Shen, M. M. (2013). Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell of origin model for prostate cancer heterogeneity. Nat. Cell Biol., 15: 274-283.

Delto, J.C., Kobayashi, T., Benson, M.C., McKiernan, J., and Abate-Shen, C. (2013). Preclinical analyses of intravesical chemotherapy for prevention of bladder cancer progression. Oncotarget 4: 269-276.

Julio, M. K., Shibata, M., Desai, N., Reynon, M., Halili, M. V., Hu, Y. P., Price, S. M., Abate-Shen, C. and Shen, M. M. (2013). Canonical Wnt signaling regulates Nkx3.1 expression and luminal epithelial differentiation during prostate organogenesis. Dev Dyn 242: 1160 – 1171.

Kobayashi, T., Wang, J., Al-Ahmadie, H. A. and Abate-Shen, C. (2013). ARF regulates the stability of p16 protein via REGy-Dependent Proteasome Degradation. Mol Cancer Res., 11: 828-33.

Aytes, A, Mitrofanova, A, Kinkade, CW, Lefebvre, C, Lei, M, Phelan, V, Le, HC, Koutcher, JA, Cardiff, RD, Califano, A, Shen, MM and Abate-Shen, C. (2013) ETV4 promotes metastasis in response to activation of PI3 kinase and Ras signaling in a mouse model of advanced prostate cancer. PNAS, 110: E3506-15.

Irshad, S., Bansal, M., Castillo-Martin, M., Aytes, A., Zheng, T., Wenske, S., Guarnieri, P., Sumazin, P., Le Magnen, C., Benson, M. C., Shen, M. M., Califano, A., and Abate-Shen, C. (2013) A molecular signature predictive of indolent prostate cancer. Sci. Transl. Med., 5: 202ra122.

Irshad, S. and Abate-Shen, C. (2013). Modeling prostate cancer in mice: Something old, something new, something premalignant, something metastatic. Cancer Metastases Rev., 32: 109-22.


Current Projects

Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor, which led to the advent of androgen-deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Our research in prostate cancer has been been focussed on elucidating principal events in cancer initiation and progression.

Modeling indolent prostate cancer in mice
Nowadays, many newly diagnosed cases of prostate cancer are low-grade and unlikely to progress to lethal tumors. Some, however, will progress but currently it is difficult to tease out the few “lethal” tumors from the many indolent ones at early stages when they might have been effectively treated. We have been using genetically engineered mouse (GEM) models to decipher mechanisms of cancer initiation and to identify biomarkers that distinguish cancer subtypes at early stages based on whether they will or will not progress to cancer.
Indeed, nearly 15 years ago, in collaboration with Michael Shen, we identified the Nkx3.1 homeobox gene as the earliest known marker of prostate epithelial differentiation and showed that its loss of function in mutant mice leads to defects in prostate development as well as predisposes to prostate cancer. Over the years, our analyses of these Nkx3.1 mutant mice have provided key insights regarding the relationship between differentiation and cancer initiation. In particular, we have found that Nkx3.1 is sufficient for prostate epithelial differentiation, while its inactivation leads to increased susceptibility to oxidative damage as well as promotion of cellular senescence. Michael Shen’s group, in collaboration with us, found that Nkx3.1 marks a rare population of luminal prostate stem cells, which can serve as a cell of origin for prostate cancer. In our current studies, we are investigating mechanisms of cancer initiation as a consequence of Nkx3.1 loss-of-function, as well as the role of microenvironment in mediating these effects.
Recently, our analysis of Nkx3.1 mutant mice as a model of indolent prostate cancer provided the foundation for our recent cross-species computational analysis in which we identified a 3-gene biomarker panel that distinguishes indolent from aggressive prostate cancer. We are currently developing this 3-gene panel as prognostic biomarkers for clinical applications in early stage prostate cancer.

Modeling advanced stages of prostate cancer in mice
While most men diagnosed with early stage prostate cancer are now essentially curable, the prognosis for men with advanced prostate cancer is much more tenuous. Advanced prostate cancer is often associated with a transition to a castration-resistant form of the disease that is highly aggressive, usually metastatic, and often fatal.
In collaboration with Michael Shen’s group, we have generated a new series of GEM models based on inducible deletion of key tumor suppressors or inducible activation of key oncogenes specifically in the prostate epithelium. These models recapitulate the various stages of advanced prostate cancer, including castration-resistance and lethal metastasis. Most of our GEM models of advanced prostate cancer have loss of function of Pten, which we have shown to be essential for castration-resistance. We have also shown that combinatorial activation of the PI3-kinase/Akt/mTOR and Raf/MEK/Erk MAP kinase signaling pathways is prevalent in advanced prostate cancer progression and consequently, pre-clinical analyses of these GEM models have demonstrated the efficacy of combinatorial targeting of these signaling pathways for treatment of advanced prostate cancer. In our current studies, we are evaluating the efficacy of combinatorial targeting these pathways together with agents that target androgen receptor signaling for treatment of castration-resistant prostate cancer and to understand mechanisms of resistance.
We have also been developing GEM models of metastatic prostate cancer. In particular, we have generated a mouse model, based on inactivation of Pten combined with activation of Kras, which displays a fully penetrant metastatic prostate cancer phenotype and shares molecular features in common with lethal prostate cancer in humans. Lineage-tracing analyses of metastases in this GEM model in vivo, combined with molecular investigations, led to the identification of the ETS gene, ETV4, as an essential gene for metastasis in the mice and conserved in human prostate cancer. A major focus of our current studies is to elucidate essential drivers of prostate cancer metastasis and particularly potential targets for therapeutic intervention.
A major focus of our current studies has been to apply systems biology approaches to effectively integrate molecular insights from our GEM models to human cancer. In collaboration with the laboratories of Andrea Califano and Michael Shen, we have generated “interactomes” (or regulatory networks) for both mouse and human prostate cancer and have used these regulatory networks to pursue cross-species analyses. These studies have led to the identification of synergistic regulators of advanced prostate cancer that are robust biomarkers of aggressive human prostate cancer. Additionally, we are using these interactomes to integrate analyses of drug response in GEM models to human cancer, with the ultimate goal of “personalizing” treatment for more effective therapeutic management of human cancer.

Modeling invasive bladder cancer in mice
Bladder cancer is a critical problem for human health, as it is the fifth most common cancer occurring worldwide and a major cause of morbidity and mortality. While, superficial bladder tumors, which account for ~80% of bladder neoplasms, have good clinical outcome, the remaining ~20% with invasive disease have high rates of mortality and few effective treatment options. Despite its significant clinical relevance, the molecular biology of bladder cancer has been relatively understudied.
We developed a strategy to achieve gene recombination specifically in the bladder urothelium by introducing an adenovirus-expressing Cre recombinase into the bladder lumen. Using this approach, we showed that combinatorial loss of function of p53 and Pten leads to invasive bladder tumors that share histological and molecular features of human bladder cancer as pathways associated with loss/mutation of p53 and Pten are often de-regulated in human bladder cancer. In particular, we have found that mTOR signaling pathway is activated in muscle invasive bladder cancer, and consequently that intravesical delivery of Rapamycin directly into the bladder lumen is an effective treatment for invasive bladder cancer. These findings demonstrate the potential therapeutic benefit of inhibiting mTOR signaling for treatment of patients at high risk for developing invasive bladder cancer and support a more wide-spread use of intravesical delivery of therapeutic agents for treatment of high-risk bladder cancer patients.


Honors and Awards

American Cancer Society (ACS) Research Professor

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