Human liver organoids for disease modeling of fibrolamellar carcinoma

Narayan, Nicole J.C.; Requena, David; Lalazar, Gadi; Ramos‐Espiritu, Lavoisier; Ng, Denise; Levin, Solomon E.; Shebl, Bassem; Wang, Ruisi; Hammond, William J.; Saltsman, James A.; Gehart, Helmuth; Torbenson, Michael; LaQuaglia, Michael P.; Simon, Sanford M.

doi:10.1016/j.stemcr.2022.06.003

Cited by 16 publications

(9 citation statements)

References 56 publications

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“…We were fortunate to have the collaboration of Hans Clevers, a pioneer of organoid development. Together, we made and validated organoids both of fibrolamellar and hepatoblastoma 27,28 . Yet another approach is to implant cells from human FLC tumours into mice with compromised immune systems to form what are called patient-derived xenografts (PDXs).…”

Section: Advocacy Versus Privacymentioning

confidence: 99%

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Simon

2023

Nat Rev Cancer

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The fight against rare cancers faces myriad challenges, including missed or wrong diagnoses, lack of information and diagnostic tools, too few samples and too little funding. Yet many advances in cancer biology, such as the realization that there are tumour suppressor genes, have come from studying well-defined, albeit rare, cancers. Fibrolamellar hepatocellular carcinoma (FLC), a typically lethal liver cancer, mainly affects adolescents and young adults. FLC is both rare, 1 in 5 million, and problematic to diagnose. From the paucity of data, it was not known whether FLC was one cancer or a collection with similar phenotypes, or whether it was genetically inherited or the result of a somatic mutation. A personal journey through a decade of work reveals answers to these questions and a road map of steps and missteps in our fight against a rare cancer.

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Section: Advocacy Versus Privacymentioning

confidence: 99%

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Simon

2023

Nat Rev Cancer

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“…Previous work has provided insights into the molecular characteristics of tumor tissues 5 , 6 , 10 , 11 , 17 , 36 , 37 , 43 – 45 , but mechanistic studies into how FLC mutations affect healthy liver cells and how different genetic backgrounds collectively drive FLC remains unknown. Relevant existing experimental human models include the growth of PDX lines and tumor organoids, both derived from a few primary or metastatic tumor samples 4 , 21 – 24 . Here, by using CRISPR-engineering in human hepatocyte organoids, we studied and compared the impact of introducing different FLC genetic backgrounds on the molecular and phenotypic behavior of human hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Transcriptomic profiling of a PDX line displayed strong resemblance with biliary tree stem cells, and thus a progenitor cell capable of dual-lineage differentiation was instead proposed as putative cell-of-origin 21 . A recent study reported the establishment of 3D organoid cultures from primary and metastatic FLC tissues harboring the DNAJB1-PRKACA fus background 24 . Relevant human models to address the impact of FLC mutations on initially healthy liver cells to probe the molecular and phenotypic consequences would help understanding the process and requirements of FLC tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss

et al. 2023

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Fibrolamellar carcinoma (FLC) is a lethal primary liver cancer, affecting young patients in absence of chronic liver disease. Molecular understanding of FLC tumorigenesis is limited, partly due to the scarcity of experimental models. Here, we CRISPR-engineer human hepatocyte organoids to recreate different FLC backgrounds, including the predominant genetic alteration, the DNAJB1-PRKACA fusion, as well as a recently reported background of FLC-like tumors, encompassing inactivating mutations of BAP1 and PRKAR2A. Phenotypic characterizations and comparisons with primary FLC tumor samples revealed mutant organoid-tumor similarities. All FLC mutations caused hepatocyte dedifferentiation, yet only combined loss of BAP1 and PRKAR2A resulted in hepatocyte transdifferentiation into liver ductal/progenitor-like cells that could exclusively grow in a ductal cell environment. BAP1-mutant hepatocytes represent primed cells attempting to proliferate in this cAMP-stimulating environment, but require concomitant PRKAR2A loss to overcome cell cycle arrest. In all analyses, DNAJB1-PRKACAfus organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.

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“…A growing number of organoid and patient-derived xenograft models are being developed from patients with FLC to investigate key features of this disease (see [29,30,45,46,[63][64][65][66] for recent examples). We describe the growth of mouse FLC-like cell models in culture and as allografts.…”

Section: Discussionmentioning

confidence: 99%

Development of pre-clinical murine models for fibrolamellar hepatocellular carcinoma

He,

Coles,

Hartmann

et al. 2023

Preprint

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Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of cancer that affects primarily adolescents and young adults. FLC tumors are typically associated with an intrachromosomal deletion resulting in expression of a fusion protein between the chaperone DNAJ1B and the protein kinase PKA. FLC is challenging to study because of its rarity and limited pre-clinical models. Here we developed a novel transgenic mouse model of FLC. In this model, DNAJ1B-PKA expression in the liver of mouse embryos results in perinatal lethality while DNAJ1B-PKA expression in the liver of adult mice initiates tumors resembling FLC at low penetrance. Some of these tumors can be serially propagated in 3D cultures and in allografts, including in syngeneic hosts. One such model shows growth inhibition upon treatment with the CDK4/6 inhibitor palbociclib. New pre-clinical models of FLC will provide novel insights into the biology of this rare cancer and may help identify novel therapeutic strategies.

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Human liver organoids for disease modeling of fibrolamellar carcinoma

Cited by 16 publications

References 56 publications

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss

Development of pre-clinical murine models for fibrolamellar hepatocellular carcinoma

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