Organoid Cultures Derived from Patients with Advanced Prostate Cancer

Abstract

Summary The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D “organoid” system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression and CHD1 loss. Whole exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as of DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies.

A patient‐derived explant (PDE) model of hormone‐dependent cancer

“…The appreciation for patient‐derived models in this context is increasing rapidly in parallel with organoid and PDX techniques. The major difference between explant and organoid culture is that the latter are generated from tumors that are minced and enzymatically digested to dissociate cells for seeding in Matrigel (Gao et al ., 2014), whereas explant tissue is cultured in its native format without disruption to the tissue architecture or tumor microenvironment. In this way, explants are more analogous to PDX models but without the significant associated costs, timeframes, and complication of infiltrating mouse stroma (Whittle et al ., 2015).…”

“…The use of immortalized human cell line models for investigating novel therapies in vitro or in vivo is convenient but also a major reason for the high failure of new drugs entering clinical trials. To move toward more clinically relevant model systems, researchers have adopted patient‐derived approaches such as organoids (Drost et al ., 2016; Gao et al ., 2014) and xenografts (PDX) (Lawrence et al ., 2013; Wang et al ., 2005; Whittle et al ., 2015). We report an alternative approach of culturing freshly resected breast and prostate cancer tissue as patient‐derived explants (PDE).…”

Translational potential of human brain organoids

“…This landmark paper established a novel experimental paradigm for generating tissue organoids. Subsequent studies worldwide confirmed the generalizability of such approach to human stem cells, and produced organoids of a variety of organ types including colon,11 intestine,12 prostate,13, 14 fallopian tube,15 stomach,16 liver,17, 18 kidney,19 lung,20 and brain 8…”

Organoids reveal cancer dynamics

“…Organoid techniques were initially developed to grow normal tissues in vitro in 3D, but have proved equally useful for propagating clinical tumour specimens [8][9][10][11][12] . Roerink et al set out to examine intratumoral hetero geneity using organoids.…”

“…A hybrid EMT state, also known as a metastable state or partial EMT, in which individual cells express both epithelial and mesenchymal markers, has often been observed in carcinoma 7 , developmental processes and wound healing 8 . One model for how EMT might occur is that cells make a gradual transition from one state to the other along a continuous spectrum of change in which cells lose epithelial characteristics and concurrently gain mesenchymal ones.…”