Prostate Stroma Increases the Viability and Maintains the Branching Phenotype of Human Prostate Organoids

Richards, Zachary; McCray, Tara; Marsili, Joseph; Zenner, Morgan L.; Manlucu, Jacob T.; Garcia, Jason; Kajdacsy-Balla, André; Murray, Marcus; Voisine, Cindy; Murphy, Adam B.; Abdulkadir, Sarki A.; Prins, Gail S.; Nonn, Larisa

doi:10.1016/j.isci.2019.01.028

Cited by 64 publications

(76 citation statements)

References 34 publications

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“…This physical attachment allowed the CAFs to supply the organoids with the niche factor necessary for their growth. In agreement with these findings, a 3D co-culture model of prostate organoids and stroma enhanced the formation and induced a change in the morphology of organoids from spherical shape in mono-culture to branched acini structure in co-culture, more similar to what is observed in vivo (Richards et al, 2019).…”

Section: Co-cultures With Cafssupporting

confidence: 83%

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

Fiorini

Veghini

Corbo

2020

Front. Cell Dev. Biol.

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Homotypic and heterotypic interactions between cells are of crucial importance in multicellular organisms for the maintenance of physiological functions. Accordingly, changes in cell-to-cell communication contribute significantly to tumor development. Cancer cells engage the different components of the tumor microenvironment (TME) to support malignant proliferation, escape immune control, and favor metastatic spreading. The interaction between cancerous and non-cancerous cell types within tumors occurs in many ways, including physical contact and paracrine signaling. Furthermore, local and long-range transfer of biologically active molecules (e.g., DNA, RNA, and proteins) can be mediated by small extracellular vesicles (EVs) and this has been shown to influence many aspects of tumor progression. As it stands, there is a critical need for suitable experimental systems that enable modeling the cell-to-cell communications occurring in cancer. Given their intrinsic complexity, animal models represent the ideal system to study cell-to-cell interaction between different cell types; however, they might make difficult to assess individual contribution to a given phenotype. On the other hand, simplest experimental models (i.e., in vitro culture systems) might be of great use when weighing individual contributions to a given phenomenon, yet it is imperative that they share a considerable number of features with human cancer. Of the many culture systems available to the scientific community, patient-derived organoids already proved to faithfully recapitulate many of the traits of patients' disease, including genetic heterogeneity and response to therapy. The organoid technology offers several advantages over conventional monolayer cell cultures, including the preservation of the topology of cell-to-cell and cell-to-matrix interactions as observed in vivo. Several studies have shown that organoid cultures can be successfully used to study interaction between cancer cells and cellular components of the TME. Here, we discuss the potential of using organoids to model the interplay between cancer and non-cancer cells in order to unveil biological mechanisms involved in cancers initiation and progression, which might ultimately lead to the identification of novel intervention strategy for those diseases.

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Section: Co-cultures With Cafssupporting

confidence: 83%

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

Fiorini

Veghini

Corbo

2020

Front. Cell Dev. Biol.

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“…Organoid drug screens on primary or early metastasis PCa are required to assess functional correlation between drug sensitivity and therapy resistance/clonal selection. Additional steps to improve the assay for routine use include the reintroduction of stromal and immune cell types in organoid cultures [59] and the optimization of drug dosage in vitro assays to guide their clinical use [60].…”

Section: Ar-blocker Enzalutamide Was Effective Only In the Androgen-dmentioning

confidence: 99%

Patient-derived xenografts and organoids model therapy response in prostate cancer

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa).RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX-and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds.This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds. Conflict of interest and Disclosure Statement:The authors declare no conflict of interest.

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“…The archetypal histology of the human prostate is described by extensive acinar-tubular branching; however, previous organoid culture approaches have generated only acinar types of histology . Our work has shown that iPSC-derived organoid cultures also recapitulate this characteristic branching morphology, which is likely to be related to the stromal compartment (derived from the iPSCs) that is known to support branching (Richards et al, 2019) .…”

Section: Discussionmentioning

confidence: 57%

High-throughput propagation of human prostate tissue from induced-pluripotent stem cells

Hepburn

Curry

Moad

et al. 2019

Preprint

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Primary culture of human prostate organoids is slow, inefficient and laborious. To overcome this, we demonstrate a new high-throughput model where rapidly proliferating and easily handled induced pluripotent stem cells, for the first time, enable generation of human prostate tissue in vivo and in vitro.Using a co-culture technique with urogenital sinus mesenchyme, we recapitulated the in situ prostate histology, including the stromal compartment and the full spectrum of epithelial differentiation. This approach overcomes major limitations in primary cultures of human prostate stem, luminal and neuroendocrine cells, as well as the stromal microenvironment. These models provide new opportunities to study prostate development, homeostasis and disease.

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Prostate Stroma Increases the Viability and Maintains the Branching Phenotype of Human Prostate Organoids

Cited by 64 publications

References 34 publications

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

Modeling Cell Communication in Cancer With Organoids: Making the Complex Simple

Patient-derived xenografts and organoids model therapy response in prostate cancer

High-throughput propagation of human prostate tissue from induced-pluripotent stem cells

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