title: A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions.
abstract: Patient-derived xenograft (PDX) models better represent human cancer than traditional cell lines. However, the complex in vivo environment makes it challenging to employ PDX models to investigate tumor-stromal interactions, such as those that mediate prostate cancer (PCa) bone metastasis. Thus, we engineered a defined three-dimensional (3D) hydrogel system capable of supporting the co-culture of PCa PDX cells and osteoblastic cells to recapitulate the PCa-osteoblast unit within the bone metastatic microenvironment in vitro. Our 3D model not only maintained cell viability but also preserved the typical osteogenic phenotype of PCa PDX cells. Additionally, co-culture cellularity was maintained over that of either cell type cultured alone, suggesting that the PCa-osteoblast cross-talk supports PCa progression in bone, as is hypothesized to occur in patients with prostatic bone metastasis. Strikingly, osteoblastic cells co-cultured with PCa PDX tumoroids organized around the tumoroids, closely mimicking the architecture of PCa metastases in bone. Finally, tumor-stromal signaling mediated by the fibroblast growth factor axis tightly paralleled that in the in vivo counterpart. Together, these findings indicate that this 3D PCa PDX model recapitulates important pathological properties of PCa bone metastasis, and validate the use of this model for controlled and systematic interrogation of complex in vivo tumor-stromal interactions.
authors.affiliation: Department of Bioengineering, Rice University, 6500 Main Street, Houston, TX 77030, USA.
authors.forename: Eliza L S
authors.initials: EL
authors.lastname: Fong
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xinhai
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of BioSciences, Rice University, 6500 Main Street, Houston, TX 77030, USA.
authors.forename: Micaela
authors.initials: M
authors.lastname: Morgado
authors.affiliation: Department of Bioengineering, Rice University, 6500 Main Street, Houston, TX 77030, USA.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Mikos
authors.affiliation: Department of BioSciences, Rice University, 6500 Main Street, Houston, TX 77030, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Harrington
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: nnavone@mdanderson.org.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.affiliation: Department of Bioengineering, Rice University, 6500 Main Street, Houston, TX 77030, USA; Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of BioSciences, Rice University, 6500 Main Street, Houston, TX 77030, USA. Electronic address: farachca@rice.edu.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Farach-Carson
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001859:Bone Neoplasms / Q000556:secondary*; D002450:Cell Communication; D018929:Cell Culture Techniques / Q000295:instrumentation; D002460:Cell Line; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D020100:Hydrogels; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology; D010455:Peptides / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D015363:Quinolones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D017154:Stromal Cells / Q000473:pathology*; D023822:Tissue Engineering; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D020100:Hydrogels; D009363:Neoplasm Proteins; D010455:Peptides; D015363:Quinolones; D034741:RNA, Small Interfering; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Co-culture; Hydrogel; Model; Osteoblasts; Patient-derived xenograft; Prostate cancer; Three-dimensional