Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells

Breunig, Markus; Merkle, Jessica; Wagner, Martin; Melzer, Michael Karl; Barth, Thomas F.E.; Engleitner, Thomas; Krumm, Johannes; Wiedenmann, Sandra; Cohrs, Christian M.; Perkhofer, Lukas; Jain, Gaurav; Krüger, Jana; Hermann, Patrick C.; Schmid, Maximilian; Madácsy, Tamara; Varga, Árpád; Griger, Joscha; Azoitei, Ninel; Müller, Martin C.; Wessely, Oliver; Robey, Pamela Gehron; Heller, Sandra; Dantes, Zahra; Reichert, Maximilian; Güneş, Çagatay; Bolenz, Christian; Kühn, Florian; Maléth, József; Speier, Stephan; Liebau, Stefan; Sipos, Bence; Küster, Bernhard; Seufferlein, Thomas; Rad, Roland; Meier, Matthias; Hohwieler, Meike; Kleger, Alexander

doi:10.1016/j.stem.2021.03.005

Cited by 63 publications

(149 citation statements)

References 126 publications

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“…Using these lineage-committed organoids, we demonstrate that KRAS G12D and GNAS R201C have lineage-specific effects in culture and in vivo. Our results are consistent with Breunig et al (Breunig et al, 2021) and together identify the pancreatic progenitor cell derived exocrine organoid platform as an opportunity to understand mechanisms regulating lineage commitment in the human exocrine pancreas and to model pancreatic cancer initiation and progression in culture.…”

Section: Discussionsupporting

confidence: 92%

Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids

Huang¹,

Desai²,

Conrad³

et al. 2021

Cell Stem Cell

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Summary The exocrine pancreas, consisting of ducts and acini, is the site of origin of pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Our understanding of the genesis and progression of human pancreatic diseases, including PDAC, is limited because of challenges in maintaining human acinar and ductal cells in culture. Here we report induction of human pluripotent stem cells toward pancreatic ductal and acinar organoids that recapitulate properties of the neonatal exocrine pancreas. Expression of the PDAC-associated oncogene GNAS R201C induces cystic growth more effectively in ductal than acinar organoids, whereas KRAS G12D is more effective in modeling cancer in vivo when expressed in acinar compared with ductal organoids. KRAS G12D , but not GNAS R201C , induces acinar-to-ductal metaplasia-like changes in culture and in vivo . We develop a renewable source of ductal and acinar organoids for modeling exocrine development and diseases and demonstrate lineage tropism and plasticity for oncogene action in the human pancreas.

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Section: Discussionsupporting

confidence: 92%

Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids

Huang¹,

Desai²,

Conrad³

et al. 2021

Cell Stem Cell

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“…Recently, two separate groups from Huang et al and Breunig et al have generated the hPSC-based pancreatic duct-like and acinus-like organoids, which have recapitulated the properties of neonatal exocrine pancreas. Using these models introducing the PDAC-associated oncogene mutations, they revealed that GNAS R201C and KRAS G12D have lineage-dependent effects on PDAC formation in vitro and in vivo, GNAS R201C mutated in ductal organoids induced cystic growth more effectively than acinar organoids, whereas KRAS G12D expressed in acinar organoids is more effective to induce acinar-to-ductal metaplasia-like changes and model PDAC in vivo [ 119 , 120 ]. This study highlighted the advantages of hPSC-derived organoids in modeling tumor progression of heterogeneity.…”

Section: Bos For Modeling Tumor Initiation Progression and Invasionmentioning

confidence: 99%

Human pluripotent stem cell-derived brain organoids as in vitro models for studying neural disorders and cancer

Luo

2021

Cell Biosci

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The sheer complexities of brain and resource limitation of human brain tissue greatly hamper our understanding of the brain disorders and cancers. Recently developed three-dimensional (3D) brain organoids (BOs) are self-organized and spontaneously differentiated from human pluripotent stem cells (hPSCs) in vitro, which exhibit similar features with cell type diversity, structural organization, and functional connectivity as the developing human brain. Based on these characteristics, hPSC-derived BOs (hPDBOs) provide new opportunities to recapitulate the complicated processes during brain development, neurodegenerative disorders, and brain cancers in vitro. In this review, we will provide an overview of existing BO models and summarize the applications of this technology in modeling the neural disorders and cancers. Furthermore, we will discuss the challenges associated with their use as in vitro models for disease modeling and the potential future direction.

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“…Moreover, the use of patient-derived induced pluripotent stem cells (iPSCs) allows disease modeling in a patient-specific background. Our recently developed differentiation protocol enables the generation of pancreatic duct-like organoids (PDLOs) from pluripotent stem cells carrying specific cancer-associated mutations [13,14]. In contrast to end-stage analysis in tumor organoids [15], such an hPSC-based model system offers the potential of in vitro investigation of cancer evolution in a stage-specific and timed manner [13,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…Our recently developed differentiation protocol enables the generation of pancreatic duct-like organoids (PDLOs) from pluripotent stem cells carrying specific cancer-associated mutations [13,14]. In contrast to end-stage analysis in tumor organoids [15], such an hPSC-based model system offers the potential of in vitro investigation of cancer evolution in a stage-specific and timed manner [13,16,17]. In addition, orthotopic xenotransplantation allows the generation of human PDAC-like tumors in mice for disease modeling in vivo [13,17,18].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to end-stage analysis in tumor organoids [15], such an hPSC-based model system offers the potential of in vitro investigation of cancer evolution in a stage-specific and timed manner [13,16,17]. In addition, orthotopic xenotransplantation allows the generation of human PDAC-like tumors in mice for disease modeling in vivo [13,17,18].…”

Section: Introductionmentioning

confidence: 99%

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CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome

Merkle

Breunig

Schmid

et al. 2021

Cancers

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Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRASG12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRASG12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells.

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Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells

Cited by 63 publications

References 126 publications

Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids

Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids

Human pluripotent stem cell-derived brain organoids as in vitro models for studying neural disorders and cancer

CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome

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