Srinivas Nandana, Ph.D.
Signaling mechanisms that mediate Prostate Cancer bone metastasis, Development of Mouse Models to closely mimic Prostate Cancer metastatic progression, Chemokine Signaling in driving Prostate Cancer metastatic homing to the bone, Role of the immune microenvironment in Prostate Cancer bone metastasis
Bone metastasis is a crucial turning point in the progression of prostate cancer and is seen in > 90% of the lethal cases. The 5-year survival rate for men diagnosed with primary or localized prostate cancer is nearly 100%, while only 28% of men diagnosed with metastatic prostate cancer survive beyond 5 years. It is therefore of pivotal importance to identify the molecular mechanisms by which primary prostate cancer cells metastasize to the bone. The overarching research endeavors in our lab focus on studying the biology, signaling network, and tumor-microenvironment interactions involved in the manifestation of bone metastasis during prostate cancer lethal progression, with the goal of developing novel therapeutics that target the disease.
Signaling Mechanisms mediating Prostate Cancer Metastasis:
Using a variety of pre-clinical mouse models - xenograft, syngeneic, and transgenic mice - we are interested in deciphering the molecular and signaling mechanisms that mediate prostate cancer progression including homing and growth of prostate cancer cells (Seed) in the bone (Soil). We recently identified a novel mechanism in which TBX2, a T-box transcription factor, coordinately regulates prostate cancer bone metastasis during all the 3 vital steps - i.e. colonization, homing, and growth in the bone - through its downstream effectors WNT3A, MMPs and IL-6 (see Cancer Research, 2017, 77(6):1331-1344 for details). Our findings highlight TBX2 as a novel therapeutic target upstream of WNT3A and underscore the potential of WNT3A antagonists that could be used for the treatment of metastasis and skeletal complications in prostate cancer patients. We are currently investigating additional molecular mechanisms upstream and downstream of TBX2 that mediate prostate cancer bone metastasis.
Generate Mouse Models to better mimic Prostate Cancer Bone Metastasis:
A major hurdle in our understanding of the prostate cancer metastatic cascade is the lack of an animal model that can spontaneously recapitulate all the steps of this process in an in vivo experimental model with an intact immune system. To address this major limitation, we have recently developed a syngeneic mouse model that develops a high frequency of bone metastasis in immune-competent hosts. This approach provides us with a novel tool to investigate cancer homing and interaction with the bone in an immune-competent host microenvironment more closely mimicking human physiology. Additionally, we are working towards our goal of generating a transgenic mouse model of prostate cancer bone metastasis that can mimic all the steps in the bone metastatic cascade.
Role of the Immune Microenvironment in Prostate Cancer Bone Metastatic Cascade:
The basic principle involves delineating cancer cell chemotaxis and also how the host immunity determines prostate cancer metastasis to bone. By utilizing the syngeneic mice that we developed, we are investigating the contribution of the individual immune cell populations including B cells in orchestrating prostate cancer bone metastasis. Further, data generated utilizing our immune-intact mouse model shows that the CXCL12/CXCR4 and RANKL/RANK pathways co-operate with each other to drive prostate cancer bone metastasis. The central hypothesis of this project is that the CXCL12/CXCR4 axis is pivotal for the homing of prostate cancer cells to the bone, and the RANKL/RANK pathway is crucial for the growth and colonization of prostate cancer cells in the bone microenvironment; that these pathways converge in their downstream signaling; and that this signaling convergence is critical for the establishment of human prostate cancer bone metastasis.
- Tripathi M. *, Nandana S. *, Billet S., Cavassani K., Chung L.W.K., Posadas E.M., Bhowmick N.A. Modulation of cabozantinib efficacy by the prostate tumor microenvironment. Oncotarget, 2017; Sep 23; 8(50): 87891-87902 (*contributed equally)
- Nandana S.*#, Tripathi M.*, Duan P., Chu C.Y., Mishra R., Liu C., Jin R., Yamashita H., Zayzafoon M., Bhowmick N.A., Zhau H.E., Matusik R.J. and Chung L.W.K.# Bone metastasis of prostate cancer can be therapeutically targeted at the TBX2-WNT signaling axis. Cancer Research, 2017; Mar 15; 77(6):1331-1344 (*contributed equally, # denotes co-corresponding authorship)
- Gururajan M., Cavassani K.A., Sievert M., Duan P., Lichterman J., Huang J.M., Smith B., You S., Nandana S., Chu G.C., Mink S., Josson S., Liu C., Morello M., Jones L.W., Kim J., Freeman M.R., Bhowmick N., Zhau H.E., Chung L.W., Posadas E.M. SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer. Oncotarget, 2015 Nov 26, Vol 6, No 42: 44072-83
- Josson S., Gururajan M., Hu P., Shao C., Chu G.Y., Zhau H.E., Liu C., Lao K., Lu C.L., Lu Y.T., Lichterman J., Nandana S., Li Q., Rogatko A., Berel D., Posadas E.M., Fazli L., Sareen D., Chung L.W. miR-409-3p/5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of prostate cancer. Clinical Cancer Res, 2014 Sep 1; 20(17): 4636-46
- Nandana S., and Chung L.W.K. Prostate Cancer Progression and Metastasis: Current and Potential Therapeutic Pathways & Mouse Models in Pre-Clinical Research. American Journal of Clinical and Experimental Urology, 2014 Jul 12; 2(2): 92-101
- Nandana S., Ellwood-Yen K., Sawyers C.L., Wills M.L., Weidow B., Case T.C., Vasioukhin V., and Matusik R.J. Hepsin co-operates with myc in the progression of adenocarcinoma in a prostate cancer mouse model. Prostate, 2010 May, 70(6):591-600
- Degraff D.J., Yu X., Sun Q., Mirosevich J., Jin R.J., Wang Y., Gupta A., Nandana S., Case T., Paul M., Huang H.Y., Shapiro E., Logan S., Suzuki K., Orgebin-Crist M.C., Matusik R.J. The role of Foxa proteins in the regulation of androgen receptor activity, Chapter 18, 587-615, 2009 Androgen Action in Prostate Cancer, Tindall D.J. and Mohler J.
- Yi Y., Nandana S., Case T.C., Nelson C., Radmilovic T., Matusik R.J., Tsuchiya K.D. Candidate metastasis suppressor genes uncovered by array comparative genomic hybridization in a mouse allograft model of Prostate Cancer. Molecular Cytogenetics, 2009 Sep, 2:18
- Tripathi M., Nandana S., Yamashita H., Kirchhofer D. and Quaranta V. Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression. Journal of Biological Chemistry, 2008 Nov, 283 (45):30576-84
- Matusik R.J., Jin R.J., Sun Q., Wang Y., Yu X., Gupta A., Nandana S., Case T.C., Paul M., Mirosevich J., Oottamasathien S., Thomas J. Prostate epithelial cell fate. Differentiation, 2008 Jul, 76:(6) 682-98
- Levititin F., Weiss M., Hahn Y., Stern O., Papke R.L., Matusik R.J., Nandana S., Ziv R, Pichinuk E., Salame S., Bera T, Vincent J, Lee B., Pastan I, and Wreschner D.H. PATE Gene Clusters Code for Multiple, Secreted TFP/Ly-6/uPAR Proteins that are expressed in reproductive and neuron-rich tissues and possess neuromodulatory activity. Journal of Biological Chemistry. 2008 Jun, 283(24):16928-16939
- Kenchappa P., Yadav A., Singh G., Nandana S., Banerjee K. Rescue of TNF alpha inhibited neuronal cells by IGF-1 involves Akt and c-Jun N-terminal kinases. Journal of Neuroscience Research. Mar 2004, 76(4) 466-474