Manisha Tripathi, Ph.D.
Role of the Tumor Microenvironment (TME) including immune cells in Prostate Cancer progression, Cross-talk between the epithelia and Cancer Associated Fibroblasts (CAFs) in Castrate Resistant Prostate Cancer (CRPC), Role of the TME in mediating drug efficacy in Prostate Cancer, Role of TME in drug resistance to androgen deprivation therapy (ADT) in Prostate Cancer
It is now widely known that the constant cross-talk between the tumor and its surrounding microenvironment fuels cancer progression. However, most therapeutic modalities are predominantly targeted towards the tumor cells. In an effort towards finding more effective and holistic treatment options against prostate cancer, we are investigating how the tumor cells talk with the tumor microenvironment (TME). Targeting the TME involves a deeper understanding of the reciprocal interactions that take place within the milieu. The overall focus in our lab is to delineate the cellular and molecular mechanisms of cross-talk between prostate cancer and TME with particular emphasis on investigating how cancer associated fibroblasts (CAFs) and the tumor associated macrophages (TAMs) contribute to the disease progression. Our approach to studying these interactions involves the use of various in vitro and in vivo tools including 3-D culture systems, xenograft and transgenic mouse models, and patient-derived xenograft (PDX) models.
Specific areas of study include:
Signaling Crosstalk between the Epithelia and the Cancer Associated Fibroblasts in
Castrate Resistant Prostate Cancer:
Despite the fact that androgen deprivation therapy (ADT) is widely used to treat human prostate cancer, in almost all the cases, the disease progresses to castrate resistant prostate cancer (CRPC) – a major treatment challenge in the clinic. We have recently found a vicious cycle of cross-talk between Hippo signaling in prostate cancer and the Notch pathway in the TME, and our observations suggest that that this vicious cycle actively fuels CRPC. Using various model systems, we are elucidating the role of Hippo/Notch signaling cross-talk in the TME that is mediated by CAFs and TAMs during CRPC progression, with the goal of therapeutically targeting this cross-talk.
Delineation of the role played by the Prostate Tumor Immune Microenvironment in shaping
We are interested in elucidating how the host microenvironment including the immune cells have the potential to affect the efficacy of therapeutic modalities in human prostate cancer. In a recent study, we found a correlation between positive therapeutic response and M1 macrophage polarization in circulating monocytes in cabozantinib-treated metastatic CRPC patients. This study provides a deeper understanding of the immune components within the tumor microenvironment, and our findings underscore the need to re-evaluate therapeutic strategies in prostate cancer and identify suitable patient populations based on TME responses.
- Cavassani K, Rebecca M, David H, Chen J, Alexander M, Tripathi M, Martins G, Timothy C, You S, Hogaboam C, Bhowmick N, Posadas E. Circulating monocytes from prostate cancer patients promote invasion and motility of epithelial cells. Cancer Medicine. 2018 August.
- Kato M, Placencio VR, Madhav A, Haldar S, Tripathi M, Billet S, Mishra R, Smith B, Rohena-Rivera K, Agarwal P, Duong F, Angara B, Hickok D, Liu Z, Bhowmick N. Heterogeneous cancer associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner. Oncogene. 2018 July.
- Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P, Duong F, Angara B, Tripathi M, Liu Z, Gottlieb RA, Wagner S, Posadas EM, Bhowmick NA. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018 Jul 26. pii: 99397.
- 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. Manuscript Accepted in Oncotarget, 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, 77(6):1331-1344; Mar 15, 2017 (*contributed equally).
- Haldar S., Dru C., Mishra R., Tripathi M., Angara B., Duong F., Fernandez A., Arditi M., Bhowmick N.A. Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. Scientific Reports, 6: 39257; DOI: 10.1038/srep39257, 2016.
- Qi J., Tripathi M., Mishra R., Sahgal N., Fazil L., Ettinger S., Placzek W.J., Claps G., Chung L.W.K., Bowtell D., Gleave M., Bhowmick N.A., and Ronai Z.A. The E3 Ubiquitin Ligase Siah2 Contributes to Castration-Resistant Prostate Cancer by Regulation of Androgen Receptor Transcriptional Activity. Cancer Cell, Volume 23, Issue 3: March 18, 2013.
- Tripathi M., Billet S., and Bhowmick N.A. Understanding the role of stromal fibroblasts in cancer progression. Cell Adhesion & Migration. 1; 6(3): 231-5, May 2012.
- Tripathi M., Potdar A., Yamashita H., Weidow B., Cummings P.T., Kirchhofer D., and Quaranta V. Laminin-332 cleavage by Matriptase alters motility parameters of prostate cancer cells. The Prostate, 1; 71 (2): 184-96 Feb, 2011.
- Yamashita H., Tripathi M., Jourquin J., Kam Y., Liu S., Weidow B., and Quaranta V. Lysophosphatidic acid upregulates laminin-332 expression during A431 cell colony dispersal. Journal of Oncology, Article ID 107075, Aug, 2010.
- Yamashita H., Tripathi M., Harris M., Ronca F., Liu S, and Quaranta V. A recombinant fragment of laminin-332 directs integrin α3β1-dependent cell binding, spreading, and migration. Biomaterials, 31 (19): 5110-21, Mar 26, 2010.
- Yamashita H., Shang M., Tripathi M., Jourquin J., Liu S., Weidow B., and Quaranta V. Epitope Mapping of Function-blocking Monoclonal Antibody CM6 Suggests a "Weak" Integrin Binding Site on the Laminin-332 LG2 Domain. Journal of Cellular Physiology 223 (3): 541-548, Mar 18, 2010.
- 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, 283 (45): 30576-84. Nov, 2008.
- Dey P.*, Tripathi M.*, and Batra J.K. Involvement of loops L2 and L4 of ribonucleolytic toxin restrictocin in its functional activity. Protein and Peptide Letters, 14: 125-129, 2007 (*contributed equally).