Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies

Nuciforo, Sandro; Fofana, Isabel; Matter, Matthias S.; Blumer, Tanja; Calabrese, Diego; Boldanova, Tujana; Piscuoglio, Salvatore; Wieland, Stefan; Ringnalda, Femke; Schwank, Gerald; Terracciano, Luigi; Ng, Charlotte K.Y.; Heim, Markus H.

doi:10.1016/j.celrep.2018.07.001

Cited by 345 publications

(351 citation statements)

References 48 publications

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“…One case of third-and fourth-line chemotherapy also exhibited lack of sensitivity to docetaxel. Our results highlight the applicability of patientderived organoid drug screens to predict clinical outcome [20] and their correlation with genomic and transcriptomic features of the primary tumor, as shown in recent studies for lung [56], gastrointestinal cancer [20], hepatocellular carcinoma [57] and ovarian cancer [58]. The panel of drugs can be adapted depending on the individual patient profile e.g.…”

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

confidence: 61%

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

confidence: 61%

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

Karkampouna

Manna

Filippo

et al. 2020

Preprint

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“…In C284b, the correlation between the human HCC and the PDX tumors was weaker than in other cases. This is likely explained by the loss of the trabecular growth pattern in the PDX tumor and the lower tumor content in the biopsy (<30% according to WES‐based CNA analysis; data not shown). Furthermore, HCC‐specific expression of somatic mutations in cancer genes was maintained in the corresponding PDX models.…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular Carcinoma Xenografts Established From Needle Biopsies Preserve the Characteristics of the Originating Tumors

et al. 2019

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related deaths worldwide. Treatment options for patients with advanced‐stage disease are limited. A major obstacle in drug development is the lack of an in vivo model that accurately reflects the broad spectrum of human HCC. Patient‐derived xenograft (PDX) tumor mouse models could overcome the limitations of cancer cell lines. PDX tumors maintain the genetic and histologic heterogeneity of the originating tumors and are used for preclinical drug development in various cancers. Controversy exists about their genetic and molecular stability through serial passaging in mice. We aimed to establish PDX models from human HCC biopsies and to characterize their histologic and molecular stability during serial passaging. A total of 54 human HCC needle biopsies that were derived from patients with various underlying liver diseases and tumor stages were transplanted subcutaneously into immunodeficient, nonobese, diabetic/severe combined immunodeficiency gamma‐c mice; 11 successfully engrafted. All successfully transplanted HCCs were Edmondson grade III or IV. HCC PDX tumors retained the histopathologic, transcriptomic, and genomic characteristics of the original HCC biopsies over 6 generations of retransplantation. These characteristics included Edmondson grade, expression of tumor markers, tumor gene signature, tumor‐associated mutations, and copy number alterations. Conclusion: PDX mouse models can be established from undifferentiated HCCs, with an overall success rate of approximately 20%. The transplanted tumors represent the entire spectrum of the molecular landscape of HCCs and preserve the characteristics of the originating tumors through serial passaging. HCC PDX models are a promising tool for preclinical personalized drug development.

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“…Indeed, routine liver biopsy remains the gold standard for diagnosis of NASH and if performed optimally poses minimal risk to the patient (23,27,28). Indeed needle biopsies have recently been reported to be sufficient for derivation of liver cancer organoids from patient liver (29) despite the fact that they actually grow more slowly in organoid culture than normal liver organoids (30). We noticed that normal donor liver derived organoids are not only bipotent but can repeatedly convert from the biliary state to the hepatic state and back to the biliary state, closely reflecting the situation in vivo, as several careful lineage tracing studies in mice have shown (16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

NASH patient liver derived organoids exhibit patient specific NASH phenotypes and drug responses

McCarron

Bathon

Abbey

et al. 2019

Preprint

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One Sentence Summary: NASH patient liver derived organoids replicate NASH liver phenotypes in a patient specific manner and exhibit profound differences in their response to drugs that are currently used in NASH clinical trials. Abstract:To determine if patient liver derived organoids can in principle be a useful experimental model for non alcoholic staetohepatitis (NASH), we derived to our knowledge for the first time bipotent ductal organoids from endstage NASH patient livers, and for comparison from normal donor livers. We found that all tested NASH liver derived organoids exhibited a profound failure to dedifferentiate from the hepatic state back to the biliary state, consistent with the known poor regenerative capacity of NASH livers. Indeed, RNAseq on all tested NASH organoid populations confirmed down regulation of multiple cell cycle pathways. NASH liver derived hepatically differentiated organoids can slowly expand as monolayers, significantly simplifying microscopic quantitation: The monolayers show variable, but overall significantly increased lipid droplet accumulation in response to free fatty acids. Transcriptome analysis of NASH organoids reveals strong upregulation of a wide variety of pro inflammatory pathways in a NASH patient specific manner. Surprisingly, NASH liver derived organoids are highly diverse not only regarding their cytochrome cytochrome p450 metabolism and inflammatory response, but also react differentially to known antisteatotic, anti inflammatory and antifibrotic drugs, raising the possibility of using NASH patient liver biopsy derived organoids for personalized drug screening and therapy.

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Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies

Cited by 345 publications

References 48 publications

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

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

Hepatocellular Carcinoma Xenografts Established From Needle Biopsies Preserve the Characteristics of the Originating Tumors

NASH patient liver derived organoids exhibit patient specific NASH phenotypes and drug responses

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