Cynthia Miranti, PhD

Professor, Cellular and Molecular Medicine
Professor, BIO5 Institute
Chair, Cancer Biology Graduate Interdisciplinary Program
Co-Program Leader, Cancer Biology Research Program at UACC
Lead, Prostate Cancer Working Group at UACC

B.A. in Microbiology - Southern Illinois University
M.S. in Microbiology - Colorado State University
Ph.D. in Biochemistry - Harvard Medical School
Postdoctoral Fellow - ARIAD Pharmaceuticals and Harvard Medical School
Assistant/Associate Professor - Van Andel Research Institute
Professor, Dept of Cellular and Molecular Medicine, University of Arizona

Research Interests: 

The research in my lab is focused on understanding the mechanisms by which the tumor microenvironment influences prostate cancer development, metastasis, and hormonal drug resistance. Our approach is to understand the normal biology of the prostate gland and its microenvironment, as well as the bone environment, to inform on the mechanisms by which tumor cells remodel and use that environment to develop, metastasize, and acquire hormonal resistance. We use a combination of genetics, cell biology, and molecular biology in in vitro and in vivo models of prostate cancer to understand basic underlying mechanisms. Our hypotheses and approaches are based solidly on observations derived from clinical disease and are aimed at addressing clinically important problems in prostate cancer. Our current research program revolves around three primary areas of interest.

Prostate-on-a-Chip
We are using bioengineering approaches to develop human in vitro models that better represent human prostate cancer as it is seen in the clinic. We developed the first Prostate-on-a-Chip model that recapitulates the development and differentiation processes that occur in the normal prostate gland. We are using this model to define how signals from oncogene-transformed epithelium influence androgen signaling in the underlying stroma and how dysregulation of that stromal signaling potentiates prostate cancer progression. We are also using this model to define the underlying genetic and epigenetic events that are dysregulated during prostate cancer development. Our long-term goal is to use these models to define new biomarkers that can help prostate cancer patients make better decisions about treatment.

Bone Metastasis
For prostate cancer patients who develop metastatic disease, the primary site of metastasis is the bone. We are investigating the signaling pathways that promote and maintain bone metastases. Key pathways we have identified in this process include integrin α6, CD82, Notch3, and the androgen receptor (AR). Current studies are focused on defining the relationship between Snail and AR how they cooperatively work together to control tumor cell dissemination and metastatic outgrowth. We are particularly interested in how the bone microenvironment influences metastatic processes.

Castration-Resistant Prostate Cancer (CRPC)
Anti-androgen therapy that targets the androgen receptor (AR) is the mainstay for prostate cancer patients with bone metastatic disease. Unfortunately, the majority of these patients will relapse with drug resistance, referred to as CRPC. Interestingly, AR is still the major driver of CRPC, the gene being mutated, amplified, or activated in ways that no longer require androgen. We are investigating how signals from the bone tumor microenvironment potentiate AR and integrin α6 signaling to perpetuate tumor growth and tumor survival during hormonal drug resistance. We discovered that the hypoxic environment of the bone contributes to drug resistance through induction of Bnip3 and PIM kinase via AR and integrin α6 to promote mitophagy and anti-ROS signaling. We are developing novel therapies to target AR, integrin α6, and PIM and testing them in human patient-derived bone metastasis models.

Molecular Medicine Grad Program: 
Yes

Bibliography

2021

Watson, M. J., P. L. Berger, K. Banerjee, S. B. Frank, L. Tang, S. S. Ganguly, G. Hostetter, M. Winn, and C. K. Miranti, "Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation.", Oncogene, 04/2021. PMID: 33846571
Casillas, A. L., S. S. Chauhan, R. K. Toth, A. G. Sainz, A. N. Clements, C. C. Jensen, P. R. Langlais, C. K. Miranti, A. E. Cress, and N. A. Warfel, "Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors.", Oncogene, 2021 Jul 02. PMID: 34211090

2020

Dodla, P., V. Bhoopalan, S. Kean Khoo, C. Miranti, and S. Sridhar, "Gene expression analysis of human prostate cell lines with and without tumor metastasis suppressor CD82.", BMC Cancer, vol. 20, issue 1, pp. 1211, 12/2020. PMCID: PMC7724878  PMID: 33298014
Hall, A., T. Fontelonga, A. Wright, K. Bugda Gwilt, J. Widrick, A. Pasut, F. Villa, C. K. Miranti, D. Gibbs, E. Jiang, et al., "Tetraspanin CD82 is necessary for muscle stem cell activation and supports dystrophic muscle function.", Skelet Muscle, vol. 10, issue 1, pp. 34, 11/2020. PMCID: PMC7693590  PMID: 33243288
Nollet, E. A., M. Cardo-Vila, S. S. Ganguly, J. D. Tran, V. V. Schulz, A. Cress, E. Corey, and C. K. Miranti, "Androgen receptor-induced integrin α6β1 and Bnip3 promote survival and resistance to PI3K inhibitors in castration-resistant prostate cancer.", Oncogene, vol. 39, issue 31, pp. 5390-5404, 07/2020. PMCID: PMC7395876  PMID: 32565538
Miranti, C. K., S. Moore, Y. Kim, V. Reddy Chappeta, K. Wu, B. De, V. Gokhale, L. H. Hurley, and E. M. Reyes-Reyes, "Nucleolin represses transcription of the androgen receptor gene through a G-quadruplex.", Oncotarget, vol. 11, issue 19, pp. 1758-1776, 05/2020. PMCID: PMC7233804  PMID: 32477465

2019

Toth, R. K., J. D. Tran, M. T. Muldong, E. A. Nollet, V. V. Schulz, C. C. Jensen, L. A. Hazlehurst, E. Corey, D. Durden, C. Jamieson, et al., "Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC.", Am J Clin Exp Urol, vol. 7, issue 4, pp. 297-312, 08/2019. PMCID: PMC6734039  PMID: 31511835
Rubenstein, C. S., J. M. C. Gard, M. Wang, J. E. McGrath, N. Ingabire, J. P. Hinton, K. D. Marr, S. J. Simpson, R. B. Nagle, C. K. Miranti, et al., "Gene editing of α6 integrin inhibits muscle invasive networks and increases cell-cell biophysical properties in prostate cancer.", Cancer Res, 07/2019. PMID: 31337652
Ganguly, S. S., G. Hostetter, L. Tang, S. B. Frank, K. Saboda, R. Mehra, L. Wang, X. Li, E. T. Keller, and C. K. Miranti, "Notch3 promotes prostate cancer-induced bone lesion development via MMP-3.", Oncogene, 08/2019. PMID: 31467432
Khan, N. S., D. P. Lukason, M. Feliu, R. A. Ward, A. K. Lord, J. L. Reedy, Z. G. Ramirez-Ortiz, J. M. Tam, P. V. Kasperkovitz, P. E. Negoro, et al., "CD82 controls CpG-dependent TLR9 signaling.", FASEB J, pp. fj201901547R, 08/2019. PMID: 31408613
Tam, J. M., J. L. Reedy, D. P. Lukason, S. G. Kuna, M. Acharya, N. S. Khan, P. E. Negoro, S. Xu, R. A. Ward, M. B. Feldman, et al., "Tetraspanin CD82 Organizes Dectin-1 into Signaling Domains to Mediate Cellular Responses to Candida albicans.", J Immunol, vol. 202, issue 11, pp. 3256-3266, 06/2019. PMCID: PMC6529278  PMID: 31010852
Jiang, L., F. Ivich, S. Tahsin, M. Tran, S. B. Frank, C. K. Miranti, and Y. Zohar, "Human stroma and epithelium co-culture in a microfluidic model of a human prostate gland.", Biomicrofluidics, vol. 13, issue 6, pp. 064116, 11/2019. PMCID: PMC6867939  PMID: 31768202
Bergsma, A., S. S. Ganguly, M. E. Wiegand, D. Dick, B. O. Williams, and C. K. Miranti, "Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82.", Bone Rep, vol. 10, pp. 100196, 06/2019. PMCID: PMC6369370  PMID: 30788390

2018

Das, L., J. M. C. Gard, R. Prekeris, R. B. Nagle, C. Morrissey, B. S. Knudsen, C. K. Miranti, and A. E. Cress, "Novel Regulation of Integrin Trafficking by Rab11-FIP5 in Aggressive Prostate Cancer.", Mol Cancer Res, vol. 16, issue 8, pp. 1319-1331, 2018 08. PMCID: PMC6369592  PMID: 29759989
Bergsma, A., S. S. Ganguly, D. Dick, B. O. Williams, and C. K. Miranti, "Global deletion of tetraspanin CD82 attenuates bone growth and enhances bone marrow adipogenesis.", Bone, vol. 113, pp. 105-113, 2018 08. PMID: 29782939

2017

Frank, S. B., P. L. Berger, M. Ljungman, and C. K. Miranti, "Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC.", J Cell Sci, vol. 130, issue 11, pp. 1952-1964, 2017 Jun 01. PMID: 28446540
Frank, S. B., V. V. Schulz, and C. K. Miranti, "A streamlined method for the design and cloning of shRNAs into an optimized Dox-inducible lentiviral vector.", BMC Biotechnol, vol. 17, issue 1, pp. 24, 2017 02 28. PMCID: PMC5331646  PMID: 28245848
Berger, P. L., M. E. Winn, and C. K. Miranti, "Miz1, a Novel Target of ING4, Can Drive Prostate Luminal Epithelial Cell Differentiation.", Prostate, vol. 77, issue 1, pp. 49-59, 2017 01. PMID: 27527891

2016

Zarif, J. C., and C. K. Miranti, "The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance.", Cell Signal, vol. 28, issue 5, pp. 348-356, 2016 May. PMCID: PMC4788534  PMID: 26829214
Tesfay, L., V. V. Schulz, S. B. Frank, L. E. Lamb, and C. K. Miranti, "Receptor tyrosine kinase Met promotes cell survival via kinase-independent maintenance of integrin α3β1.", Mol Biol Cell, vol. 27, issue 15, pp. 2493-504, 2016 08 01. PMCID: PMC4966988  PMID: 27307589

2015

Uchtmann, K., E. R. Park, A. Bergsma, J. Segula, M. J. Edick, and C. K. Miranti, "Homozygous loss of mouse tetraspanin CD82 enhances integrin αIIbβ3 expression and clot retraction in platelets.", Exp Cell Res, vol. 339, issue 2, pp. 261-9, 2015 Dec 10. PMID: 26562164
Zarif, J. C., L. E. Lamb, V. V. Schulz, E. A. Nollet, and C. K. Miranti, "Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.", Oncotarget, vol. 6, issue 9, pp. 6862-76, 2015 Mar 30. PMCID: PMC4466655  PMID: 25730905

2014

Berger, P. L., S. B. Frank, V. V. Schulz, E. A. Nollet, M. J. Edick, B. Holly, T-T. A. Chang, G. Hostetter, S. Kim, and C. K. Miranti, "Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis.", Cancer Res, vol. 74, issue 12, pp. 3357-68, 2014 Jun 15. PMCID: PMC4066454  PMID: 24762396
Ganguly, S. S., X. Li, and C. K. Miranti, "The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis.", Front Oncol, vol. 4, pp. 364, 2014. PMCID: PMC4266028  PMID: 25566502

2013

Frank, S. B., and C. K. Miranti, "Disruption of prostate epithelial differentiation pathways and prostate cancer development.", Front Oncol, vol. 3, pp. 273, 2013 Oct 31. PMCID: PMC3813973  PMID: 24199173

2011

Lamb, L. E., J. C. Zarif, and C. K. Miranti, "The androgen receptor induces integrin α6β1 to promote prostate tumor cell survival via NF-κB and Bcl-xL Independently of PI3K signaling.", Cancer Res, vol. 71, issue 7, pp. 2739-49, 2011 Apr 01. PMID: 21310825

2010

Lamb, L. E., B. S. Knudsen, and C. K. Miranti, "E-cadherin-mediated survival of androgen-receptor-expressing secretory prostate epithelial cells derived from a stratified in vitro differentiation model.", J Cell Sci, vol. 123, issue Pt 2, pp. 266-76, 2010 Jan 15. PMID: 20048343