<i>Kras</i>-driven heterotopic tumor development from hepatobiliary organoids

Ochiai, Masako; Yoshihara, Yasunori; Maru, Yoshiaki; Matsuura, Tetsuya; Izumiya, Masashi; Imai, Toshio; Hippo, Yoshitaka

doi:10.1093/carcin/bgz024

Cited by 29 publications

(53 citation statements)

References 41 publications

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“…Growth of orthotopic and s.c. allotransplants was monitored by longitudinal luciferase bioimaging and caliper measurement, respectively. Control organoids were not tumorigenic, in agreement with previous reports 8,9 . Instead, allotransplants of F-BICC1 and F-TACC3 organoids yielded progressively growing tumors at either orthotopic or s.c. transplantation sites (Figure 2A, B), with 100% penetrance (Supplementary Table 1).…”

Section: Tp53 Null Mouse Liver Organoids Transduced With Fgfr2-bicc1 supporting

confidence: 92%

FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling

Cristinziano

Porru

Lamberti

et al. 2020

Preprint

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All Authors, except M.J.B., have no personal, professional or financial conflicts to disclose. M.J.B. AbstractBackground and aims. About 15% of intrahepatic cholangiocarcinoma (iCCA) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), most often in concert with mutationally inactivated TP53, CDKN2A or BAP1. FFs span residues 1-768 of FGFR2 fused to sequences encoded by any of a long list (>60) of partner genes, a configuration sufficient to ignite oncogenic FF activation. In line, FGFR-specific tyrosine kinase inhibitors (F-TKI) were shown to provide clinical benefit in FF+ iCCA, although responses were partial and/or limited by resistance mechanisms, including the FF V565F gatekeeper mutation. Herein we present an FF-driven murine iCCA model and exploit its potential for pre-clinical studies on FF therapeutic targeting.Methods. Four iCCA FFs carrying different fusion sequences were expressed in Tp53 -/mouse liver organoids. Tumorigenic properties of genetically modified liver organoids were assessed by intrahepatic/subcutaneous transplantation in immuno-deficient mice. Cellular models derived from neoplastic lesions were exploited for pre-clinical studies. Results. Tumors diagnosed as CCA were obtained upon transplantation of FF-expressing liver organoids. The penetrance of this tumorigenic phenotype was influenced by FF identity. Tumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or presence of V565F mutation. Double blockade of FF-Ras-Erk pathway by concomitant pharmacological inhibition of FFs and Mek1/2 provided greater therapeutic efficacy than single agent F-TKI in vitro and in vivo. Conclusions. FF-driven iCCA pathogenesis was successfully modelled in murine Tp53 -/background. This model revealed biological heterogeneity among structurally different FFs. Double blockade of FF-Erk signaling deserves consideration for improving precision-based approaches against human FF+ iCCA.

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Section: Tp53 Null Mouse Liver Organoids Transduced With Fgfr2-bicc1 supporting

confidence: 92%

FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling

Cristinziano

Porru

Lamberti

et al. 2020

Preprint

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“…Although the negative results of focus formation assay of ADAP1 fusion genes may implicate that they have no role in the pathogenesis of CRC and are merely “passenger” alterations, another possibility is that tumor‐promoting features of ADAP1 fusion genes are cell‐context dependent and 3T3 fibroblast was not a suitable cell type to be assayed. Therefore, further investigation as to whether ADAP1 fusion genes contribute to the pathogenesis of CRC is warranted, by using other cells such as primary epithelial intestinal or colonic cells, especially under 3D organoid culture conditions …”

Section: Discussionmentioning

confidence: 99%

Genomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes

et al. 2019

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Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole‐exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage‐matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A‐to‐C nucleotide change in the context of “AAG” was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such “LM‐associated” genes were overrepresented for extracellular matrix‐receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1‐substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis.

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“…To date, it has been applied to various research fields, including infectious disease models, developmental biology, and epithelial regeneration . We also reported the establishment of murine organoid‐based carcinogenesis models for intestine, lung, hepatobiliary tract, and pancreas . These organoid culture techniques have now become common for patient‐derived samples from diverse types of cancer, which revealed that tumor‐derived organoids basically retained the morphology and genetic aberrations of the original tumors .…”

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of patient‐derived organoids from a young patient with cervical clear cell carcinoma

et al. 2019

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Cervical clear cell carcinoma (cCCC) constitutes an extremely rare subtype of cervical cancer. Consequently, its pathogenesis remains largely unknown, with no cell lines established from primary tumors. Here, we report the first establishment of cCCC organoids, from biopsy samples of a 23‐year‐old patient diagnosed with cCCC. By applying a protocol that we recently optimized for gynecological tumors, we were able to propagate a patient‐derived cell line (PDC) for more than 6 months as organoids. This PDC tolerated cryopreservation and proliferated either as spheroids or adherent cells, and developed xenografts in immunodeficient mice, ensuring robust utility as a cell line. Intriguingly, the resected tumor focally contained serous carcinoma (SC) in a tiny protruding lesion. Both organoids and derivative xenografts resembled the CCC component of the original tumor in histology, immunostaining profile, and genome‐wide copy number changes, including focal gain of MET. Genomic analysis revealed that both organoids and the CCC component harbored only a few mutations, of which 2 mutations were shared in common. In contrast, the SC component showed a mutator‐phenotype and prominent genome instability along with biallelic inactivation of TP53, but none of them were found in organoids or the CCC component. The PDC proved sensitive to major chemotherapeutic agents and MET inhibitors. These observations clearly indicated that the PDC, designated as YMC7, can be used as a novel cCCC cell line and provide novel insights into the pathogenesis of mixed cervical adenocarcinoma. As a valuable resource for rare cancer, it will likely contribute to investigations in many fields.

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Kras-driven heterotopic tumor development from hepatobiliary organoids

Cited by 29 publications

References 41 publications

FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling

FGFR2 fusion protein-driven mouse models of intrahepatic cholangiocarcinoma unveil a necessary role for Erk signaling

Genomic profiles of colorectal carcinoma with liver metastases and newly identified fusion genes

Establishment and characterization of patient‐derived organoids from a young patient with cervical clear cell carcinoma

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