Kaustubh Datta

Associate Professor, Biochemistry and Molecular Biology

Kaustubh Datta, PhDPhone: 402-559-7404 (Office)
402-559-4074 (Lab)
Fax: 402-559-6650
Email: kaustubh.datta@unmc.edu 

Education/Training:
Ph.D., Indian Institute of Chemical Biology, Calcutta, INDIA, 1999
Dr. Datta has received his post-doctoral training at Beth Israel Medical Center, Harvard Medical School, Boston in the field of tumor angiogenesis.

Research:

Research Opportunities in my laboratory:
Graduate students (basic and clinical)
Post-doctoral fellows
Undergraduate students, summer research
Motivated students are welcome for rotation in our laboratory.

Research Interest: Molecular mechanisms of cancer progression and metastasis

VEGF-C/Neuropilin-2 axis in cancer: Our laboratory studies the role of angiogenic growth factors in promoting the survival and metastasis of cancer. We are particularly interested in the function of vascular endothelial growth factor-C (VEGF-C) and its receptor neuropilin-2 in promoting metastasis in prostate cancer. Our laboratory and others have reported an increased expression of both VEGF-C and neuropilin-2 in prostate cancer cells compared to the adjacent normal cells (as shown in Figures 1 and 2), suggesting their cancer-specific roles.

Figure 1: Increased expression Neoplastic prostate glands are positive for neuropilin-2 staining, whereas normal of VEGF-C in human prostate glands have no or very faint staining for Neuropilin-2.Figure 2: Neuropilin-2 (receptor for VEGF-C) is expressed in higher level in human prostate cancer
Figure 1: Increased expression Neoplastic prostate glands are positive for neuropilin-2 staining, whereas normal of VEGF-C in human prostate glands have no or very faint staining for Neuropilin-2.

Figure 2: Neuropilin-2 (receptor for VEGF-C) is expressed in higher level in human prostate cancer

Known Function of VEGF-C: VEGF-C is known to be a potent growth factor on lymphatic endothelial cells and induces the formation of new lymphatic vessel in both physiological and pathological conditions, a process known as lymphangiogenesis. It is believed that by inducing lymphangiogenesis in a tumor microenvironment, VEGF-C facilitates metastasis to adjacent lymph nodes. New enlarged lymphatic vessels at the periphery (peritumoral) and/or inside (intratumoral) of VEGF-C expressing primary tumors have been observed in human tumor specimens and also in tumor xenografts. Tumor cells from the primary tumor enter into the lymphatics through the enlarged, highly permeable junctions of newly-developed lymphatic endothelium and drain into the lymph nodes (as shown in figure 3). As lymph node metastasis is a poor prognostic factor for several cancers, studies on the function of VEGF-C should provide a thorough understanding of the process of lymph node metastasis and its relation with cancer progression and metastasis. VEGF-C usually acts through a tyrosine kinase receptor Flt-4 (Fms-related tyrosine kinase 4), also known as VEGF receptor -3 (VEGFR-3), as well as through a non-tyrosine kinase receptor neuropilin-2. Both the receptors are expressed in lymphatic endothelial cells. Interestingly, high expression of neuropilin-2 is also observed in many cancer cells including prostate cancer (as shown in figure 2).

Figure 3: Involvement of lymphangiogenesis in lymphnode metastasis (Schematic representation).

Figure 3: Involvement of lymphangiogenesis in lymph node metastasis (Schematic representation).

Mechanism of VEGF-C synthesis in prostate cancer: Defining the molecular mechanisms by which VEGF-C synthesis is regulated in prostate cancer is important not only for the understanding of VEGF-C biology in prostate cancer but also to develop therapeutic target against this growth factor. Our laboratory observed a negative regulation of VEGF-C synthesis in prostate cancer cells by androgen. While withdrawal of androgen inhibited VEGF-A synthesis in prostate cancer cell, it favored increased synthesis of both VEGF-C protein and mRNA. The prostate specific homeobox protein NKX3.1 was found to negatively regulate VEGF-C synthesis by binding to a specific promoter site on the VEGF-C gene and recruiting histone deacetylase 1 (HDAC1), thereby inhibiting its transcription. Loss of NKX3.1 protein has been observed in tissues from advanced-stage prostate cancer patients. NKX3.1 was also found to be negatively regulated by androgen. Thus, withdrawal of androgen reduces the NKX3.1 levels in prostate cancer, thereby facilitating VEGF-C synthesis. Androgen withdrawal also activates Ras like oncogene, RalA and FOXO-1 in prostate cancer cells, which induce VEGF-C synthesis (Figure 4). Therefore, the loss of NKX3.1 in concert with the activation of RalA and FOXO-1 promote high levels of VEGF-C synthesis in prostate cancer. Currently, we are interested in determining whether tissue levels of VEGF-C level are increased in prostate cancer patients treated with androgen deprivation therapy, especially in the tumor tissues of those patients with castration-resistant disease. These studies will investigate the involvement of VEGF-C in the onset of highly metastatic, castration-resistant prostate cancer.  

Figure 4: Complex regulation of VEGF-C synthesis in prostate cancer during androgen withdrawal.

Figure 4: Complex regulation of VEGF-C synthesis in prostate cancer during androgen withdrawal.

Novel function of VEGF-C/neuropilin-2 axis in prostate cancer: A number of clinical studies have examined the relationship between the lymphangiogenesis and prostate cancer lymph node metastasis. These studies produced conflicting results. Although some investigators detected lymphangiogenesis in prostate cancer tissues, which can be correlated with lymph node metastasis, others failed to observe such a correlation. Interestingly, most of the studies have observed increased expression of VEGF-C in tumor tissues of prostate cancer patients with lymph node and distant metastasis, suggesting novel functions for VEGF-C, which are independent of lymphangiogenesis, and instead are important for cancer progression. We have reported one such novel autocrine function of VEGF-C in promoting survival of prostate cancer cells during stress. Neuropilin-2, the non-tyrosine kinase receptor of VEGF-C, is crucial for this function. We have delineated the underlying molecular mechanism for this stress-resistant function of VEGF-C/neuropilin-2 axis, which protects the mTOR complex 2 (mTORC-2) from dissociation during stress and thereby maintains its activation. AKT-1, a downstream molecule of mTORC-2 thus remains in an active state and favors survival of prostate cancer cells during stress (Figure 5). Further elucidation of this signaling axis should enrich our knowledge of the stress resistant phenomenon in the metastatic cancer and may lead to the development of new prognostic markers and novel therapeutic approaches. Defining VEGF-C expression in cancer biopsy samples may have predictive value in determining the success of a treatment option. We believe that by protecting the cancer cells from stress-induced apoptosis, VEGF-C promotes cancer recurrence and metastasis. Interestingly, recent clinical studies have shown that VEGF-C expression is correlated with cancer recurrence, further supporting our findings. Our long-term goal therefore, is to understand the importance of VEGF-C as a prognostic marker as well as a therapeutic target for refractory, metastatic cancer.  

Figure 5: An autocrine function of VEGF-C in prostate cancer cells, which facilitates survival of cancer cells during stress.

Figure 5: An autocrine function of VEGF-C in prostate cancer cells, which facilitates survival of cancer cells during stress.

Publications:

Stanton M, Dutta S, Polavaranam NS, Roy S, Muders M, Datta K. The angiogenic growth factor axis in autophagic regulation. Autophagy (in press).

Stanton M, Dutta S, Zhang H, Polavaranam NS, Leontovich A, Honscheid P, Sinicrope FA, Tindall DJ, Muders MH, Datta K. (2013) Regulation of autophagy by VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Research 73(1):160-71.

Sarkar S, Dutta D, Samanta SK, Bhattacharya K, Pal BC, Li J, Datta K, Mandal C, Mandal C. (2013) Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo. Int J Cancer (132)3:695-706.

Jacob C, Baretton GB, Aust DE, Liebscher B, Datta K, Muders MH. (2011) Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients. PlosOne 6(11):e27402.

Khurana A, Liu P, Mellone P, Lorenzon L, Vincenzi B, Datta K, Yang B, Linhardt RJ, Lingle W, Chien J, Baldi A, Shridhar V. (2011) HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells. Cancer Res. 71(6):2152-61.

Datta K
, Muders MH, Zhang H, Tindall DJ. (2010). Mechanisms of lymph node metastasis in prostate cancer (review article). Future Oncology 6(5):823-36.

Muders MH, Zhang H, Wang E, Tindall Dj, Datta K. (2009). Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin comoplex-2 and AKT-1. Cancer Research 69(15):6042-8.

Sinha S, Dutta S, Datta K, Ghosh AK, Mukhopadhyay D. (2009). Von Hippel-Landau gene product modulates TIS11B expression in renal cell carcinoma: impact on vascular endothelial growth factor expression in hypoxia. J Biol Chem 284(47):32610-8.

Zhang H, Muders MH, Li J, Rinaldo F, Tindall DJ, Datta K. (2008). Loss of NKX3.1 favor NKX3.1 expression in prostate cancer. Cancer Research 68(12):8770-8.

Muders MH, Vohra PK, Dutta SK, Wang E, Ikeda Y, Wang L, Udugamasooriya DG, Memic A, Rupashinghe CN, Baretton GB, Aust DE, Langer S, Datta K, Simons M, Spaller MR, Mukhopadhyay D. (2009). Targeting GIPC-synectin in pancreatic cancer inhibits tumor growth. Clin Cancer Res 15(12):4095-103.

Rinaldo F, Li J, Wang E, Muders MH, Datta K. (2007). Ra1A regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation. Oncogene. 26(12):1731-8.

Li J, Wang E, Dutta S, Lau JS, Jiang SW, Datta K, Mukhopadhyay D. (2007). Protein kinase C-mediated modulation of FIH-1 expression by the homeodomain protein CDP/Cut/Cux. Mol Cell Biol 27(20):7345-53.

Muders MH, Dutta SK, Wang L, Lau JS, Bhattacharya R, Smyrk TC, Chair ST, Datta K, Mukhopadhyay D. (2006). Expression and regulatory role of GAIP-interacting protein GIPC in pancreatic adenocarcinoma. Cancer Res 66(21):10264-8.

Li J, Wang E, Rinaldo F, Datta K. (2005). Up-regulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway. Oncogene 24(35):5510-20.

Datta K, Mondal S, Sinha S, Li J, Wang E, Knebelmann B, Karumanchi SA, Mukhopadhyay D. (2005). Role of Elongin binding domain of Von Hippel Lindau gene product on HuR-mediated VPF/VEGF mRNA stability in renal cell carcinoma. Oncogene 24(53):7850-8.

BOOK CHAPTERS:

Datta K, Tindall DJ. (2007). Androgen Receptor. Encyclopedia of Cancer. 2nd Edition. Springer Publication.

Datta K, Tindall DJ. (2008). Prostate Cancer. Molecular Oncology: Causes of Cancer and Targets for Treatment. Cambridge University Press, New York.

Datta K, Dahlman KB, Sawyers CL, Tindall DJ. (2009). Biological Response to Androgen Withdrawal: (A) The Androgen Receptor. Recent Advances in Prostate Cancer. World Scientific, New Jersey.

Datta K, Tindall DJ. (2010). Endocrine mechanisms, androgen receptors and carcinogenesis, hormone escape. Comprehensive Textbook of Prostate Cancer. Springer Publication.

Research Grants Awarded

R01-NIH: 1RO1 CA140432-01A2
Stress Resistant Function of VEGF-C in Prostate Cancer
PI: Datta, Kaustubh
03/01/2010-02/28/2015
The major goal of this grant is to study the role of VEGF-C in protecting prostate cancer cells from oxidative stress and its implications on prostate cancer recurrence.

 

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