Cynthia Miranti, PhD

Professor, Cellular and Molecular Medicine
Program Leader, Prostate Cancer Research
Co-Program Leader, Cancer Biology Research Program
Professor, BIO5 Institute

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: 

Miranti CV

Our objective is to define how integrin interactions within the tumor microenvironment impact prostate cancer development, hormonal resistance, and metastasis. 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, acquire hormonal resistance, and metastasize. Our research is focused in three primary areas: 1) developing in vitro and in vivo models that recapitulate human disease based on clinical pathology, 2) identifying signal transduction pathway components that could serve as both clinical markers and therapeutic targets, and 3) defining the genetic/epigenetic programming involved in prostate cancer development.

Clinical Significance
• Prostate cancer remains the second-leading cancer killer of men due to the inability to cure hormone-resistant metastatic disease. Our laboratory is focused on defining the mechanisms of hormone resistance and metastasis, and we hypothesize that the tumor microenvironment plays a major role.
• We have shown that drugs which initially show promise in laboratory settings fail in clinical trials because the existing models for prostate cancer fail to adequately address the role of the tumor microenvironment. We have developed a rational approach to defining how the tumor microenvironment affects cell survival and drug resistance.
• Many men develop prostate cancer that will not progress to lethal disease, but we lack the ability to predict which tumors will progress, resulting in over-diagnosis and unnecessary treatment. We need to identify specific steps in oncogenesis that lead to aggressive disease, and we are addressing the lack of adequate models for primary disease progression by developing new ones.
• Over 80% of prostate cancers metastasize to the bone. We are developing better models to understand both normal bone development and bone/cancer cell interactions.

The AR/α6β1 Integrin Axis
We identified a novel AR survival pathway in androgen-responsive tumors whereby AR in combination with the oncogenic TMPRSS2-Erg fusion protein directly stimulates integrin α6β1 transcription and expression. Engagement of integrin α6β1 by laminin in turn stimulates NF-κB/RelA activation and subsequently increases the transcription of Bcl-xL to promote survival. In hormone-resistant tumors, this same pathway in coordination with HIF1/2 induces a second pathway involving Bnip3. Bnip3 allows for tumor survival under high oxidative stress by targeting damaged mitochondria for degradation through autophagy. The loss of Pten, which induces PI3K signaling, is common in prostate cancers, yet PI3K inhibitors alone are not effective in patients. When tumor cells are bound to laminin via integrin α6β1, they are resistant to PI3K inhibition. Blocking PI3K in combination with blocking the AR-induced integrin α6β1 pathway re-sensitizes cells to PI3K inhibition. Thus, interaction with the tumor microenvironment through AR/α6β1 is an important mechanism by which prostate tumor cells escape their reliance on PI3K signaling, and disrupting this pathway will be necessary for effectively blocking prostate cancer in vivo. Differentiation and Oncogenesis The prostate cancer field is hampered by the lack of cell models that reflect in vivo events. We developed an in vitro differentiation model in which human basal epithelial cells are differentiated into luminal cells as observed in vivo. When we engineer these cells to simultaneously overexpress Myc and TMPRSS2/Erg and inhibit Pten, we generate tumors that mimic human pathology in vivo. Moreover, these tumor cells were unable to differentiate due to loss of the chromatin reader protein ING4. We found that ING4 protein is lost in over 60% of human primary prostate cancers. We are currently determining how ING4 expression regulates chromatin and epigenetic programming to suppress tumorigenesis. CD82/KAI1 in Bone Development CD82/KAI1 is encoded by a metastasis suppressor gene whose loss in primary prostate tumors correlates with poor patient prognosis. CD82 is one of 33 tetraspanins whose functions remain enigmatic but are linked to cell adhesion. We generated CD82-null mice to better understand the normal function of CD82. Loss of CD82 in platelets enhanced clot retraction in vitro and reduced bleeding in vivo, which as due in part to an increase in platelet-specific integrin αIIbβ3 expression. We also observe defects in bone osteoclast adhesion and activation, leading to a reduced ability to degrade bone and increased bone density. Mice lacking CD82 also have a decreased ability to clear pathogens due to defects in macrophage signaling.

Miranti CVMiranti CVMiranti CVMiranti CVMiranti CV

Molecular Medicine Grad Program: 
Yes

Bibliography

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, 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, 2019 Jul 23. 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, 2019 Aug 29. PMID: 31467432
Notch3 promotes prostate cancer-induced bone lesion development via MMP-3., 2019.
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, 2019 Aug 13. 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, 2019 Jun 01. PMCID: PMC6529278  PMID: 31010852
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, 2019 Jun. 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

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
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

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

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
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

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