Professor: Brian Kirby
Project Description: Prostate cancer is the second most common cause of cancer death in Western men. The current therapies for prostate cancer involve surgery, androgen ablation, or the blockade of the androgen receptor; however, a significantly high percentage of treated prostate cancers eventually relapse. Despite its prevalence, prostate cancer has proven very difficult to propagate in vitro when taken out of patient‘s body. The absence of biomaterial tools that allow us to recapitulate human prostate cancer outside the body has hampered progress in understanding disease pathogenesis and therapy response1. In the proposed research, we will engineer click-chemistry based modular hydrogels using maleimide-functionalized polyethylene glycol and thiolated peptides that enable survival signals in advanced prostate cancer cells. Previous studies have shown that integrin, a mechano-transducer protein present on the surface of human cells, play a key role in the alteration of cellular growth and tumor progression through the regulation of gene expression, apoptosis, cell adhesion, proliferation, migration and angiogenesis. Analysis integrin subunits expression in prostate cancer shows that α6β1 and αVβ3 expression are either maintained or overexpressed in prostate cancer, and increases in lymph node metastases2,3. To determine the role of integrin specificity, human prostate cancer cells and stromal (endothelial fibroblasts) will be cultured in hydrogels with three thiol-containing ligands of varying integrin-binding specificity: (i) linear RGD oligopeptide (GRGDSPC) – primarily binds αVβ3 integrin; (ii) recombinant CCN1 binds α6β1 integrin; and (iii) GFOGER peptide (collagen-mimetic peptide) – specifically binds α2β1 integrin. The REU student will fabricate these hydrogels, with encapsulated prostate cancer cells (Kirby lab) and determine cell survival and growth as a function of time and organoid stiffness. Similar organoids have been previously developed for human lymphomas in Singh lab4,5 at Cornell, a collaborator on this project, and together we have all resources available for successful execution of the proposed research. Successful completion of the proposed work by the REU student will lead to preliminary studies that will lay the foundation of a materials-based 3D organoid system for long-term culture of prostate cancer from biopsy specimens, relapsed patients, and circulating tumor cells.6
1 Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176-187, doi:10.1016/j.cell.2014.08.016 (2014).
2 Goel, H. L., Li, J., Kogan, S. & Languino, L. R. Integrins in prostate cancer progression. Endocr Relat Cancer 15, 657-664, doi:10.1677/ERC-08-0019 (2008).
3 Cress, A. E., Rabinovitz, I., Zhu, W. & Nagle, R. B. The alpha 6 beta 1 and alpha 6 beta 4 integrins in human prostate cancer progression. Cancer metastasis reviews 14, 219-228 (1995).
4 Cayrol, F. et al. Integrin alphavbeta3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells. Blood 125, 841-851, doi:10.1182/blood-2014-07-587337 (2015).
5 Tian, Y. F. et al. Integrin-specific hydrogels as adaptable tumor organoids for malignant B and T cells. Biomaterials 73, 110-119, doi:10.1016/j.biomaterials.2015.09.007 (2015).
6 Kirby BJ, Jodari M, Loftus M, Gakhar G, Pratt ED, Chanel-Vos C, Gleghorn JP, Santana SM, Liu H, Smith JP, Navarro VN, Tagawa ST, Bander NH, Nanus DM, Giannakakou PA, “Functional Characterization of Circulating Tumor Cells with a Prostate-Cancer-Specific Microfluidic Device “, PLoS ONE, 7(4): e35976, 2012.