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Histone demethylase KDM5D drives sex-specific differences in colorectal cancer

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Telomeric Regulation of Chromosomal Instability in Colorectal Cancer

Telomere dysfunction drives chromosomal instability (CIN) during the transition from benign adenoma to malignant adenocarcinoma. While CIN provides a mutator mechanism for cancer-relevant genomic events, its role in shaping tumor biology during carcinogenesis is not well understood. Here, we explored the molecular and biological impact of telomere dysfunction and associated CIN in vivo in a faithful model of CRC. In vivo lineage tracing revealed that CIN increased neoplastic cell competition and clonal expansion through accelerated differentiation of neighboring stem cells, resulting in increased number of adenomas and decreased survival in CIN-high Apcmin mice. Mechanistically, CIN represses EZH2 leading to upregulation of secreted Wnt antagonists, which resulted in a growth advantage to CIN-high neoplastic cells. Correspondingly, pharmacological activation of intrinsic WNT signaling enhanced intestinal stem cells fitness, leading to reduced neoplastic cell clonal expansion and adenoma burden. Thus, the CIN-EZH2-WNT axis enhances intestinal cancer initiation in the nascent tumor microenvironment, providing a preventive strategy for patients harboring germline APC mutations

Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development

During liver development bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells (BECs) to ensure a functional liver required to maintain organismal homeostasis. The developmental cues controlling the differentiation of committed progenitors into these cell types, however, are incompletely understood. Here, we discover an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. Exposure of zebrafish embryos to 17β-estradiol (E2) during liver development significantly decreased hepatocyte-specific gene expression, liver size, and hepatocyte number. In contrast, pharmacological blockade of estrogen synthesis or nuclear estrogen receptor signaling enhanced liver size and hepatocyte marker expression. Transgenic reporter fish demonstrated nuclear estrogen receptor activity in the developing liver. Chemical inhibition and morpholino knockdown of nuclear estrogen receptor 2b (esr2b) increased hepatocyte gene expression and blocked the effects of E2 exposure. esr2b(−/−) mutant zebrafish exhibited significantly increased expression of hepatocyte markers with no impact on liver progenitors, other endodermal lineages or vasculature. Significantly, E2-stimulated Esr2b activity promoted biliary epithelial differentiation at the expense of hepatocyte fate, while loss of esr2b impaired biliary lineage commitment. Chemical and genetic epistasis studies identified bone morphogenetic protein (BMP) signaling as a mediator of the estrogen effects. The divergent impact of estrogen on hepatobiliary fate was confirmed in a human hepatoblast cell line, indicating the relevance of this pathway for human liver development. CONCLUSION: Our studies identify E2, esr2b and downstream BMP activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant clinical implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy

Estrogen Activation of G-Protein–Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes

Background & Aims: Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC) and often have increased serum levels of estrogen. It is not clear how estrogen promotes hepatic growth. We investigated the effects of estrogen on hepatocyte proliferation during zebrafish development, liver regeneration, and carcinogenesis. We also studied human hepatocytes and liver tissues. Methods: Zebrafish were exposed to selective modifiers of estrogen signaling at larval and adult stages. Liver growth was assessed by gene expression, fluorescent imaging, and histologic analyses. We monitored liver regeneration after hepatocyte ablation and HCC development after administration of chemical carcinogens (dimethylbenzanthrazene). Proliferation of human hepatocytes was measured in a coculture system. We measured levels of G-protein–coupled estrogen receptor (GPER1) in HCC and nontumor liver tissues from 68 patients by immunohistochemistry. Results: Exposure to 17β-estradiol (E2) increased proliferation of hepatocytes and liver volume and mass in larval and adult zebrafish. Chemical genetic and epistasis experiments showed that GPER1 mediates the effects of E2 via the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin pathway: gper1-knockout and mtor-knockout zebrafish did not increase liver growth in response to E2. HCC samples from patients had increased levels of GPER1 compared with nontumor tissue samples; estrogen promoted proliferation of human primary hepatocytes. Estrogen accelerated hepatocarcinogenesis specifically in male zebrafish. Chemical inhibition or genetic loss of GPER1 significantly reduced tumor development in the zebrafish. Conclusions: In an analysis of zebrafish and human liver cells and tissues, we found GPER1 to be a hepatic estrogen sensor that regulates liver growth during development, regeneration, and tumorigenesis. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment. Transcript Profiling: The accession number in the Gene Expression Omnibus is GSE92544

Supplementary Table S1 from Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression

Supplementary Table S1 includes differentially expressed genes from 4 fibroblast subtypes</p

Supplementary Figure S1 from Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression

Figure S1 demonstrates the enrichment of lipid-rich CAFs within the stroma of Kras*-driven CRC.</p

Supplementary Table S4 from Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression

Supplementary Table S4 shows primers used for RT-qPCR and ChIP-qPCR</p

Supplementary Figure S3 from Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression

Figure S3 demonstrates the upregulation of proadipogenic cytokines by Kras* and its role in driving lipo-fibrogenesis.</p

Supplementary Table S5 from Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression

Supplementary Table S5 shows the human CRC clinical information.</p