Abstract 2030: Culturing patient-derived prostate cancer xenografts using a three-dimensional hydrogel system for drug testing and mechanistic studies
Authors: Fong Eliza L.S. , Martinez Mariane , Yang Jun , Chung Leland M.K. , Mikos Antonios G. , Navone Nora M. , Harrington Daniel A. , Farach-Carson Mary C. 
Published: May 2015

Advanced prostate cancer (PCa) typically metastasizes to bone and current treatments are mainly palliative. While a mechanistic understanding of PCa progression in bone is needed to develop new therapies, the complex phenotypes in PCa are poorly reflected by cell lines and cell line-based xenograft models, impeding progress in this endeavor. To overcome this limitation, a panel of PCa patient-derived xenograft (PDX) models was established at the University of Texas MD Anderson Cancer Center. While these PDX models better recapitulate the phenotypic signature of the original tumors as compared to cell lines, limitations exist, including the inability to manipulate these cells ex vivo before implantation in vivo and issues associated with the foreign animal physiology. Based on previous studies demonstrating the potential of using hyaluronan (HA)-based hydrogels for the 3D engineering of PCa cell line-derived ectotumors suitable for mechanistic studies, we evaluated the ability of these hydrogels to maintain viability of the PCa PDX tumors in vitro and optimize culture conditions.

Using the MDA PCa 183 and 118b PDX tumors as proof-of-concept, tumors freshly harvested were digested and encapsulated within a HA-based hydrogel, comprised of thiol-modified HA crosslinked with poly(ethylene glycol)-diacrylate. Tumor cells remained as multicellular aggregates or ectotumors in 3D, and were viable even up to 2 weeks in culture. Furthermore, cells were positive for Ki-67, indicating that the hydrogel system is able to retain the proliferative capacity of the tumor cells. In probing for the androgen receptor (AR) expression, we found that while the hydrogel-encapsulated MDA PCa 183 cells stained positive for AR, it was not the case for the MDA PCa 118b, as would be expected in vivo, demonstrating that the hydrogel system is also able to preserve critical phenotypic characteristics of the original tumors. Lastly, to evaluate this novel system as a potential platform for rapid drug testing, we treated the 3D PDX ectotumors to docetaxel, and compared their response against a traditional bone metastatic PCa cell line, C4-2B. Interestingly, the 3D PDX ectotumors exhibited a significantly greater resistance to the drug than the C4-2B cells, reminiscent of chemoresistant tumors in vivo.

We demonstrate for the first time that PCa PDX tumors are amenable to in vitro culture with the use of a 3D HA-based hydrogel system. The hydrogel supported the maintenance of multicellular ectotumors of PCa cells, which remained viable and phenotypically similar to the tumors of origin. Furthermore, a differential drug response to docetaxel was observed for both the 3D PCa PDX ectotumors tested as compared to the C4-2B cell line, the clinical relevance of which is currently being investigated. This model may have broad applicability for the culture of other bone metastatic cancers and enable mechanistic studies of disease biology.

Citation Format: Eliza L.S. Fong, Mariane Martinez, Jun Yang, Leland M.K. Chung, Antonios G. Mikos, Nora M. Navone, Daniel A. Harrington, Mary C. Farach-Carson. Culturing patient-derived prostate cancer xenografts using a three-dimensional hydrogel system for drug testing and mechanistic studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2030. doi:10.1158/1538-7445.AM2014-2030