Cynthia Miranti

Cynthia Miranti

Professor, Cellular and Molecular Medicine
Chair, Cancer Biology - GIDP
Co-Program Leader, Cancer Biology Research Program
Member of the Graduate Faculty
Professor, BIO5 Institute
Primary Department
Contact
(520) 626-2269

Research Interest

Research Interests 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.

Publications

Ganguly, S. S., Li, X., & Miranti, C. K. (2014). The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis. Frontiers in oncology, 4, 364.

Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.

Goren, M. B., Swendsen, C. L., Fiscus, J., & Miranti, C. (1984). Fluorescent markers for studying phagosome-lysosome fusion. Journal of leukocyte biology, 36(3), 273-92.

Lysosomotropic fluorescent aminoacridines such as acridine orange and quinacrine have achieved prominence as markers for studying lysosome-phagosomes fusion, especially in macrophages. Experiments described demonstrate that because the aminoacridines traverse biological membranes with facility, they diffuse throughout the system, and ultimately accumulate intra- or extracellularly where they are most efficiently bound. Their presence or absence in phagosomes is therefore not unequivocally indicative of fusion or nonfusion. Alternative fluorescent lysosomal markers are described, and systems defined for which the aminoacridines may probably be used with confidence.

Zarif, J. C., Lamb, L. E., Schulz, V. V., Nollet, E. A., & Miranti, C. K. (2015). Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase. Oncotarget, 6(9), 6862-76.

Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.

Putnam, A. J., Schulz, V. V., Freiter, E. M., Bill, H. M., & Miranti, C. K. (2009). Src, PKCalpha, and PKCdelta are required for alphavbeta3 integrin-mediated metastatic melanoma invasion. Cell communication and signaling : CCS, 7, 10.

Integrins, cell-surface receptors that mediate adhesive interactions between cells and the extracellular matrix (ECM), play an important role in cancer progression. Expression of the vitronectin receptor alphavbeta3 integrin correlates with increased invasive and metastatic capacity of malignant melanomas, yet it remains unclear how expression of this integrin triggers melanoma invasion and metastasis.

Zarif, J. C., & Miranti, C. K. (2016). The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance. Cellular signalling, 28(5), 348-56.

The androgen receptor (AR) remains the major oncogenic driver of prostate cancer, as evidenced by the efficacy of androgen deprivation therapy (ADT) in naïve patients, and the continued effectiveness of second generation ADTs in castration resistant disease. However, current ADTs are limited to interfering with AR ligand binding, either through suppression of androgen production or the use of competitive antagonists. Recent studies demonstrate 1) the expression of constitutively active AR splice variants that no longer depend on androgen, and 2) the ability of AR to signal in the cytoplasm independently of its transcriptional activity (non-genomic); thus highlighting the need to consider other ways to target AR. Herein, we review canonical AR signaling, but focus on AR non-genomic signaling, some of its downstream targets and how these effectors contribute to prostate cancer cell behavior. The goals of this review are to 1) re-highlight the continued importance of AR in prostate cancer as the primary driver, 2) discuss the limitations in continuing to use ligand binding as the sole targeting mechanism, 3) discuss the implications of AR non-genomic signaling in cancer progression and therapeutic resistance, and 4) address the need to consider non-genomic AR signaling mechanisms and pathways as a viable targeting strategy in combination with current therapies.