Propagation of human prostate tissue from induced pluripotent stem cells.

Anastasia C Hepburn,Laura Wilson,Omar E Franco,Susan E Crawford,Rakesh Heer,Parmveer Singh,Rebecca E Steele,Luke Gaughan,Simon W Hayward,Adriana Buskin,Emma L Curry,Ian G Mills,Craig N Robson,Mohammad Moad

doi:10.1002/sctm.19-0286

Abstract

Primary culture of human prostate organoids and patient‐derived xenografts is inefficient and has limited access to clinical tissues. This hampers their use for translational study to identify new treatments. To overcome this, we established a complementary approach where rapidly proliferating and easily handled induced pluripotent stem cells enabled the generation of human prostate tissue in vivo and in vitro. By using a coculture technique with inductive urogenital sinus mesenchyme, we comprehensively recapitulated in situ 3D prostate histology, and overcame limitations in the primary culture of human prostate stem, luminal and neuroendocrine cells, as well as the stromal microenvironment. This model now unlocks new opportunities to undertake translational studies of benign and malignant prostate disease.

Highlights

| INTRODUCTIONThe field of treatment-predictive biomarkers is rapidly developing in prostate cancer, functional tools to undertake preclinical
The field of treatment-predictive biomarkers is rapidly developing in prostate cancer, functional tools to undertake preclinicalSTEM CELLS Transl Med. 2020;1–12.wileyonlinelibrary.com/journal/sct[3 ] HEPBURN ET AL.patient-specific drug testing to more accurately guide outcomes are lacking.[1]
We demonstrate for the first time that tissue recombinants comprising human induced pluripotent stem cells (iPSCs) and rat urogenital sinus mesenchyme (UGM) generated both in vivo xenografts and in vitro prostate organoids that recreated the full breadth in situ prostate epithelial differentiation, including NE cells, as well as the stromal compartment

Summary

| INTRODUCTION

The field of treatment-predictive biomarkers is rapidly developing in prostate cancer, functional tools to undertake preclinical. Patient-specific drug testing to more accurately guide outcomes are lacking.[1] Encouragingly, the capacity to generate in vitro 3D organoid cultures is transforming the study of human diseases.[2] These structures faithfully mimic in vivo epithelial architecture and present novel opportunities for preclinical studies.[3,4] the widespread adoption of organoid culture in prostate studies is hampered by inherent shortcomings, including limited access to patient samples and the inefficient establishment of cancer organoid cultures These issues apply to the other established approach of patient-derived xenografts (PDXs).[5] Previously, successful organoid cultures were solely restricted to advanced metastatic tumors[3]; recent advances have included the addition of stromal coculture to sustain organoids derived from localized cancers.[6] In cases where longer-term cultures are established, an emerging understanding of the substantial genotypic and phenotypic drift that occurs through in vitro culture adaptation restricts their translational value.[7] Approaches that allow robust isogenic models of cancer are required[8] and the generation of tissue from pluripotent stem cells appears to be a suitable alternative. We demonstrate for the first time that tissue recombinants comprising human iPSCs and rat UGM generated both in vivo xenografts and in vitro prostate organoids that recreated the full breadth in situ prostate epithelial differentiation, including NE cells, as well as the stromal compartment

Significance statement

| RESULTS

| DISCUSSION

Findings

| CONCLUSION