β-Catenin Activation in a Novel Liver Progenitor Cell Type Is Sufficient to Cause Hepatocellular Carcinoma and Hepatoblastoma

Abstract

Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested it can also arise from fetal progenitor cells or their adult progenitor progeny. Here we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreER™-GFP BAC transgene in which a tamoxifen-inducible Cre (CreER™) and GFP are controlled by a 190kb 5′ genomic region of Cited1, a transcriptional co-activator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreER™-GFP+ progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes and SOX9+ periductal cells. By 26 weeks of age, >90% of Cited1-CreER™-GFP; Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas (HB) and lung metastases. HCC and HB resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK and PI3K/AKT/mTOR pathways, and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and HB and the development of improved therapeutics for these diseases.

Monitoring Interactions and Dynamics of Endogenous Beta-catenin With Intracellular Nanobodies in Living Cells*

“…␤-catenin as the key effector of the Wnt-pathway has been shown to modulate numerous processes including gene expression, cell proliferation, epithelial-mesenchymal transition, and tumor progression (15,27,64,65). Although the role of ␤-catenin in many cellular processes has been known for many years, we are still at the beginning of understanding how its multiple dynamic and interdependent functions are orchestrated in a spatial and temporal manner.…”

Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin

“…Moreover, as tumors frequently show hyperstabilization of Myc, mRNA profiling of HBs in the absence of follow up analysis of Myc at the protein level runs the risk of underestimating and diminishing the significance of this oncogenic transcription factor in HB (63,64). However, in light of the fact that Myc emerged as the dominant driver of HBs in this study and that Myc is overexpressed in chemically induced mouse HBs (65) as well as in HBs and HCCs that develop in mouse models following expression of oncogenes other than Myc (33,36), we propose that Myc serves as a central signaling hub for an array of other oncogenic HB drivers, making it a potentially important therapeutic target in HB that could benefit from the array of promising new drugs that target Myc and its network (66,67). Therefore, the feasibility of adopting Myc inhibitory strategies for the treatment of pediatric liver cancers and other embryonal tumors with evidence of Myc amplification/ overexpression should be explored.…”

“…However, this is unlikely to be the case in Tet-O-Myc mice or other mouse models that develop HBs following oncogene activation in mature hepatocytes (32,33), raising the question of whether HB transcriptomes and immunoprofiles reflect a hepatoblast cell of origin or the end result of dedifferentiation or reprogramming of mature hepatocytes (34). While an abundance of experimental evidence indicates that aberrant activation of Wnt/β-catenin alone is not sufficient for HB development, this has recently been challenged by the creation of a genetically engineered mouse strain that develops HBs and HCCs when mutant β-catenin is targeted to rare hepatic progenitor cells that express the CBP/p300 transcriptional coactivator protein and Myc target, Cited1 (35,36). Although the experimental strategy used to target β-catenin to the liver in this strain differs from ours, in both instances, the timing of β-catenin activation overlaps with a period of high fetal liver expression of Myc (37).…”

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

“…The company filed a first patent in 2011 on PI3K/mTOR inhibitors,334 of which one, SPR965, has reached the preclinical evaluation stage 335, 336. The compound is likely to be structurally related, if not identical to a compound recently described in a publication 337.…”