Viewing cellular origin of intrahepatic cholangiocarcinoma from perspective of tumor heterogeneity

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.

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Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

Digestive Diseases ◽

10.1159/000444562 ◽

2016 ◽

Vol 34 (4) ◽

pp. 440-451 ◽

Cited By ~ 11

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.

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The Cellular Origin in Atheromatous Lesion

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010006800x ◽

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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