Abstract 658: Elucidation of cellular origin of mouse intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion

2016 ◽  
Author(s):  
Tsuneo Ikenoue ◽  
Yumi Terakado ◽  
Kiyoshi Yamaguchi ◽  
Yoichi Furukawa
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Cellular Origin ◽  
Pten Deletion

scholarly journals A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tsuneo Ikenoue ◽  
Yumi Terakado ◽  
Hayato Nakagawa ◽  
Yohko Hikiba ◽  
Tomoaki Fujii ◽  
...  
Keyword(s):  
Mouse Model ◽  
Progenitor Cells ◽  
Intrahepatic Cholangiocarcinoma ◽  
Poor Prognosis ◽  
Cell Lineage ◽  
Therapeutic Strategies ◽  
Visualization System ◽  
Activating Mutation ◽  
Pten Deletion ◽  
A Cell

Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and its incidence is increasing worldwide. Recently, several types of cells have been considered as the origin of ICC, namely cholangiocytes, liver progenitor cells, and hepatocytes. Here, we have established a novel mouse model of ICC by liver-specific Kras activation and Pten deletion. An activating mutation of Kras in combination with deletion of Pten was introduced in embryonic hepatic bipotential progenitor cells (so-called hepatoblasts) and mature hepatocytes using the Cre-loxP system. As a result, liver-specific Kras activation and homozygous Pten deletion cooperated to induce ICCs exclusively. In contrast, Kras activation in combination with heterozygous Pten deletion induced both ICCs and HCCs, whereas Kras activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre-loxP demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific Kras activation in combination with homozygous Pten deletion should be useful for the investigation of therapeutic strategies for human ICC.

scholarly journals NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocyte reprogramming into intrahepatic cholangiocarcinoma

2020 ◽  
Author(s):  
Shikai Hu ◽  
Laura Molina ◽  
Junyan Tao ◽  
Silvia Liu ◽  
Mohammed Hassan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Epithelial Cell ◽  
Intrahepatic Cholangiocarcinoma ◽  
Clinical Relevance ◽  
Poor Prognosis ◽  
Tumor Development ◽  
Biliary Epithelial Cell ◽  
Therapeutic Implications ◽  
Cellular Origin ◽  
Downstream Effector

ABSTRACTIntrahepatic cholangiocarcinoma (ICC), a disease of poor prognosis, has increased in incidence. It is challenging to treat due to intra- and inter-tumoral heterogeneity, which in part is attributed to diverse cellular origin. Indeed, co-expression of AKT and NICD in hepatocytes (HCs) yielded ICC, with similarity to proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD regulated SOX9 and YAP1 during ICC development. Yap1 deletion or TEAD inhibition impaired HC-to-biliary epithelial cell (BEC) reprogramming and ICC proliferation; Sox9 loss repressed tumor growth; and Yap1-Sox9 combined loss abolished ICC development in AKT-NICD model. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directed HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch-dependent HC-to-ICC development, and DNMT1 re-expression restored ICC development following TEAD repression. Coexpression of DNMT1 with AKT was sufficient to induce hepatic tumor development including ICC. Thus, we have identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-driven ICC development.SIGNIFICANCEWe evaluated the clinical relevance of hepatocyte-driven ICC model and revealed critical but distinct roles of YAP1 and SOX9 in AKT-NICD-driven hepatocyte-derived ICC. We also identified NOTCH-YAP1/TEAD-DNMT1 axis as a critical driver for hepatocyte-to-ICC reprogramming, which might have biological and therapeutic implications in ICC subsets.

Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

2016 ◽  
Vol 34 (4) ◽  
pp. 440-451 ◽  
Author(s):  
Dan Høgdall ◽  
Colm J. O'Rourke ◽  
Andrzej Taranta ◽  
Douglas V.N.P. Oliveira ◽  
Jesper B. Andersen
Keyword(s):  
Patient Outcome ◽  
Intrahepatic Cholangiocarcinoma ◽  
Evolutionary Process ◽  
Disease Recurrence ◽  
Molecular Pathogenesis ◽  
Current Therapy ◽  
Cellular Origin ◽  
Pancreatic Cancers ◽  
Tumor Plasticity ◽  
Cancer Types

Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome. This was achieved for other cancers, such as breast carcinoma, facilitated by the delineation of patient subsets and of precision therapies. In iCCA, many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of tumor plasticity and the causative features driving the disease. Molecular profiling and pathological techniques have begun to underline persistent alterations that may trigger inherited drug resistance (a hallmark of hepatobiliary and pancreatic cancers), metastasis and disease recurrence. In this review, we will focus on the key molecular achievements that are currently advancing the characterization and stratification of iCCA. We will discuss current clinical practice and how genomic achievements may advance diagnosis and therapy as well as ultimately improve patient outcome.

scholarly journals Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice

2016 ◽  
Vol 213 (10) ◽  
pp. 2019-2037 ◽  
Author(s):  
Pengpeng Bi ◽  
Feng Yue ◽  
Anju Karki ◽  
Beatriz Castro ◽  
Sara E. Wirbisky ◽  
...  
Keyword(s):  
Gene Expression Signature ◽  
Lineage Tracing ◽  
Metabolic Dysfunction ◽  
Cellular Origin ◽  
Complete Penetrance ◽  
Pten Deletion ◽  
Anatomical Localization ◽  
Tumorigenic Transformation ◽  
Tissue Cancer ◽  
Notch Activation

Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction. Although concomitant Pten deletion normalizes the glucose metabolism of Ad/N1ICD mice, it dramatically accelerates the LPS prognosis and malignancy. Transcriptomes and lipidomics analyses indicate that Notch activation suppresses lipid metabolism pathways that supply ligands to Pparγ, the master regulator of adipocyte homeostasis. Accordingly, synthetic Pparγ ligand supplementation induces redifferentiation of Ad/N1ICD adipocytes and tumor cells, and prevents LPS development in Ad/N1ICD mice. Importantly, the Notch target HES1 is abundantly expressed in human LPS, and Notch inhibition suppresses the growth of human dedifferentiated LPS xenografts. Collectively, ectopic Notch activation is sufficient to induce dedifferentiation and tumorigenic transformation of mature adipocytes in mouse.

scholarly journals Erratum: Corrigendum: A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Tsuneo Ikenoue ◽  
Yumi Terakado ◽  
Hayato Nakagawa ◽  
Yohko Hikiba ◽  
Tomoaki Fujii ◽  
...  
Keyword(s):  
Mouse Model ◽  
Intrahepatic Cholangiocarcinoma ◽  
Pten Deletion

The Cellular Origin in Atheromatous Lesion

1970 ◽  
Vol 28 ◽  
pp. 202-203
Author(s):  
T. M. Murad ◽  
H. A. I. Newman ◽  
K. F. Kern
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Rabbit Aorta ◽  
Mixed Population ◽  
The Other ◽  
Cellular Origin ◽  
Ultrastructural Studies ◽  
Atherosclerotic Lesions ◽  
Show Evidence ◽  
Early Lesion

The origin of lipid containing cells in atheromatous lesion has been disputed. Geer in his study on atheromatous lesions of rabbit aorta, suggested that the early lesion is composed mainly of lipid-laden macrophages and the later lesion has a mixed population of macrophages and smooth muscle cells. Parker on the other hand, was able to show evidence that the rabbit lesion is primarily composed of lipid-laden cells of smooth muscle origin. The above studies and many others were done on an intact lesion without any attempt of cellular isolation previous to their ultrastructural studies. Cell isolation procedures have been established for atherosclerotic lesions through collagenase and elastase digestion Therefore this procedure can be utilized to identify the cells involved in rabbit atheroma.

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