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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Research Interests Our objective is to define the roles of integrins and the tumor microenvironment in 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 overdiagnosis 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/61 integrin axis The human prostate gland contains basal cells which express and use integrins to adhere to the laminin matrix in the tissue microenvironment. Basal cells do not express the androgen receptor (AR), but they differentiate into AR-expressing secretory cells that detach from the matrix and lose integrin expression. In prostate cancer, the AR-expressing tumor cells retain expression of integrin 61. We hypothesize that abnormal cross talk between AR and integrin 61 is crucial for prostate cancer development and progression to castration-resistant disease. 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 61 transcription and expression. Engagement of integrin 61 by laminin in turn stimulates NF-B/RelA activation and subsequently increases the transcription of Bcl-xL to promote survival. In castration-resistant tumors, this same pathway in coordination with HIF1/2 induces another pathway, one that involves BNIP3 and promotes survival in the presence of high oxidative stress by specifically targeting mitochondrial degradation through autophagy. 26

Miranti The loss of Pten, which leads to enhanced PI3K signaling, occurs in 60% of advanced prostate cancers, yet PI3K inhibitors are not effective in patients. When plated on laminin to engage integrin 61, tumor cells were resistant to PI3K inhibition. Blocking PI3K in combination with blocking AR, integrin 61, RelA, Bcl-xL, or BNIP3 resensitized the cells to such inhibition. Thus, interaction with the tumor microenvironment through AR/61 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 basal epithelial cells are differentiated into secretory cells that behave similarly to those in vivo; i.e., the secretory cells are marked by their loss of integrin expression and loss of adhesion to matrix. When we engineered these cells to simultaneously overexpress Myc and TMPRSS2/Erg and inhibit Pten, we generated tumorigenic cells that co-expressed integrin 61 and AR, analogous to what is seen in vivo. Moreover, these tumor cells were unable to differentiate due to loss of the chromatin-modifying protein ING4. The expression of this protein is lost in more than 60% of human 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. Their most striking phenotype was enhanced platelet clotting and reduced bleeding, as well as a twofold increase in total platelets. The increase in platelets was due to changes in megakaryocyte differentiation within the bone marrow. Other changes within the bone included an increased number of adipocytes and a reduced number of hematopoietic stem cells, as well as an increased bone density. CD82 has been implicated in osteoclast differentiation; correspondingly, there are fewer TRAP osteoclasts. We are currently determining what aspect of osteoclast differentiation is affected by CD82 loss. Recent Publications Berger, Penny L., Sander B. Frank, Veronique V. Schulz, Eric A. Nollet, Mathew J. Edick, Brittany Holly, Ting-Tung A. Chang, Galen Hostetter, Suwon Kim, et al. 2014. Transient induction of ING4 by MYC drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. Cancer Research 74(12): 3357–3368. Miranti, Cindy K., Alexis Bergsma, and Annemiek B. van Spriel. 2014. Tetraspanins as master organizers of the plasma membrane. In Cell Membrane Nanodomains: From Biochemistry to Nanoscopy, A. Cambi and D.S. Lidke, eds. Boca Raton, FL: CRC Press, pp. 59–86. Akfirat, Canan, Xiaotun Zhang, Aviva Ventura, Dror Berel, Mary E. Coangelo, Cindy K. Miranti, Maryla Krajewska, John C. Reed, Celestia S. Higano, et al. 2013. Tumour cell survival mechanisms in lethal metastatic prostate cancer differ between bone and soft tissue metastases. Journal of Pathology 230(3): 291–297. Frank, Sander B., and Cindy K. Miranti. 2013. Disruption of prostate epithelial differentiation pathways and prostate cancer development. Frontiers in Oncology 3: 273. Nollet, Eric A., and Cindy K. Miranti. 2013. Integrin and matrix regulation of autophagy and mitophagy. In Autophagy, Yannick Bailly, ed. New York: InTech, pp. 465–485. 27

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