Sa2009 – Combinatorial Blockade of De Novo Cholesterol Biosynthesis and Pcsk9 As a Synergistic Therapy Fro KrasMutant Colorectal Cancer

PURPOSE: Few studies have directly compared health care utilization, costs, and outcomes between patients treated in the US multipayer health system and Canada’s single-payer system. Using cancer registry and claims data, we assessed treatment types, costs, and survival for patients with metastatic colorectal cancer (mCRC) in Western Washington State (WW) and British Columbia (BC). MATERIALS AND METHODS: Patients age ≥ 18 years diagnosed with mCRC in 2010 and later were identified from the BC Cancer database and a regional database linking WW SEER to claims from Medicare and two large commercial insurers. Demographics, treatment characteristics, costs of systemic therapy, and survival data were obtained from these databases and compared between the two regions. RESULTS: A total of 1,592 patients from BC and 901 from WW were included in the study. Median age was similar (BC, 66 years; WW, 63 years), but patients in BC were more likely to be male (57.1% v 51.2%; P ≤ .01) and to have de novo metastatic disease (61.0% v 38.3%; P ≤ .01). The use of radiation therapy was similar between regions (BC, 31.2%; WW, 33.9%; P = .18), but primary tumor resection was more common in BC (74.1% v 66.3%; P ≤ .01) as was hepatic metastasectomy (12.4% v 2.3%; P ≤ .01). Similar percentages of patients received systemic therapy (BC, 68.8%; WW, 67.1%; P = .40), but costs were significantly higher for first-line systemic therapy in WW ($6,226 v $15,792 per patient per month; P ≤ .01). Median overall survival was similar (BC, 16.9 months; WW, 18 months). CONCLUSION: Cost of systemic therapy for mCRC was significantly higher for patients in WW than in BC, but this did not translate to a difference in overall survival.

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Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ

Nature Communications ◽

10.1038/s41467-021-22544-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Giulia Della Chiara ◽

Federica Gervasoni ◽

Michaela Fakiola ◽

Chiara Godano ◽

Claudia D’Oria ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cell ◽

De Novo ◽

Epigenetic Alterations ◽

Human Colorectal Cancer ◽

Active Chromatin ◽

Extensive Cell Death ◽

Extensive Cell ◽

Pan Cancer ◽

Tumor Maintenance

AbstractCancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.

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Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

Nature Genetics ◽

10.1038/s41588-021-00891-2 ◽

2021 ◽

Author(s):

Yannik Bollen ◽

Ellen Stelloo ◽

Petra van Leenen ◽

Myrna van den Bos ◽

Bas Ponsioen ◽

...

Keyword(s):

Colorectal Cancer ◽

Single Cell ◽

Temporal Dynamics ◽

De Novo ◽

Tumor Evolution ◽

Genome Wide ◽

Aneuploid Tumor ◽

Evolutionary Paths ◽

Tumor Biopsies ◽

Punctuated Evolution

AbstractCentral to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq—a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.

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Regulation of the SREBP transcription factors by mTORC1

Biochemical Society Transactions ◽

10.1042/bst0390495 ◽

2011 ◽

Vol 39 (2) ◽

pp. 495-499 ◽

Cited By ~ 42

Author(s):

Caroline A. Lewis ◽

Beatrice Griffiths ◽

Claudio R. Santos ◽

Mario Pende ◽

Almut Schulze

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthase ◽

Target Genes ◽

De Novo ◽

Regulatory Element ◽

Cholesterol Biosynthesis ◽

Mammalian Target Of Rapamycin ◽

Lipid Biosynthesis ◽

De Novo Lipogenesis ◽

Genes Encoding

In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers. We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth. In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.

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De novo colorectal cancer after liver and kidney transplantation–Microenvironment disturbance

Transplantation Reports ◽

10.1016/j.tpr.2020.100057 ◽

2020 ◽

Vol 5 (3) ◽

pp. 100057

Author(s):

Rui Caetano Oliveira ◽

Edgar Tavares-Silva ◽

Ana Margarida Abrantes ◽

Hugo Antunes ◽

Paulo Teixeira ◽

...

Keyword(s):

Colorectal Cancer ◽

Kidney Transplantation ◽

De Novo ◽

Liver And Kidney

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Regular exercise potentiates energetically expensive hepatic de novo lipogenesis during early weight regain

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00074.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. R684-R695

Author(s):

David M. Presby ◽

L. Allyson Checkley ◽

Matthew R. Jackman ◽

Janine A. Higgins ◽

Kenneth L. Jones ◽

...

Keyword(s):

Weight Loss ◽

Energy Expenditure ◽

De Novo ◽

Energy Gap ◽

Cholesterol Biosynthesis ◽

Density Lipoprotein ◽

De Novo Lipogenesis ◽

Positive Energy ◽

Hepatic Expression ◽

Expression Of Genes

Exercise is a potent facilitator of long-term weight loss maintenance (WLM), whereby it decreases appetite and increases energy expenditure beyond the cost of the exercise bout. We have previously shown that exercise may amplify energy expenditure through energetically expensive nutrient deposition. Therefore, we investigated the effect of exercise on hepatic de novo lipogenesis (DNL) during WLM and relapse to obesity. Obese rats were calorically restricted with (EX) or without (SED) treadmill exercise (1 h/day, 6 days/wk, 15 m/min) to induce and maintain weight loss. After 6 wk of WLM, subsets of WLM-SED and WLM-EX rats were allowed ad libitum access to food for 1 day to promote relapse (REL). An energy gap-matched group of sedentary, relapsing rats (REL-GM) were provided a diet matched to the positive energy imbalance of the REL-EX rats. During relapse, exercise increased enrichment of hepatic DN-derived lipids and induced hepatic molecular adaptations favoring DNL compared with the gap-matched controls. In the liver, compared with both REL-SED and REL-GM rats, REL-EX rats had lower hepatic expression of genes required for cholesterol biosynthesis; greater hepatic expression of genes that mediate very low-density lipoprotein synthesis and secretion; and greater mRNA expression of Cyp27a1, which encodes an enzyme involved in the biosynthesis of bile acids. Altogether, these data provide compelling evidence that the liver has an active role in exercise-mediated potentiation of energy expenditure during early relapse.

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Coxiella burnetii Expresses a Functional Δ24 Sterol Reductase

Journal of Bacteriology ◽

10.1128/jb.00818-10 ◽

2010 ◽

Vol 192 (23) ◽

pp. 6154-6159 ◽

Cited By ~ 23

Author(s):

Stacey D. Gilk ◽

Paul A. Beare ◽

Robert A. Heinzen

Keyword(s):

Host Cell ◽

Coxiella Burnetii ◽

Fluorescent Protein ◽

De Novo ◽

Cholesterol Metabolism ◽

Q Fever ◽

Parasitophorous Vacuole ◽

Cholesterol Biosynthesis ◽

Brefeldin A ◽

Ergosterol Biosynthesis

ABSTRACT Coxiella burnetii, the etiological agent of human Q fever, occupies a unique niche inside the host cell, where it replicates in a modified acidic phagolysosome or parasitophorous vacuole (PV). The PV membrane is cholesterol-rich, and inhibition of host cholesterol metabolism negatively impacts PV biogenesis and pathogen replication. The precise source(s) of PV membrane cholesterol is unknown, as is whether the bacterium actively diverts and/or modifies host cell cholesterol or sterol precursors. C. burnetii lacks enzymes for de novo cholesterol biosynthesis; however, the organism encodes a eukaryote-like Δ24 sterol reductase homolog, CBU1206. Absent in other prokaryotes, this enzyme is predicted to reduce sterol double bonds at carbon 24 in the final step of cholesterol or ergosterol biosynthesis. In the present study, we examined the functional activity of CBU1206. Amino acid alignments revealed the greatest sequence identity (51.7%) with a Δ24 sterol reductase from the soil amoeba Naegleria gruberi. CBU1206 activity was examined by expressing the protein in a Saccharomyces cerevisiae erg4 mutant under the control of a galactose-inducible promoter. Erg4 is a yeast Δ24 sterol reductase responsible for the final reduction step in ergosterol synthesis. Like Erg4-green fluorescent protein (GFP), a CBU1206-GFP fusion protein localized to the yeast endoplasmic reticulum. Heterologous expression of CBU1206 rescued S. cerevisiae erg4 sensitivity to growth in the presence of brefeldin A and cycloheximide and resulted in new synthesis of ergosterol. These data indicate CBU1206 is an active sterol reductase and suggest the enzyme may act on host sterols during C. burnetii intracellular growth.

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De Novo Fatty Acid Synthesis-Driven Sphingolipid Metabolism Promotes Metastatic Potential of Colorectal Cancer

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-18-0199 ◽

2018 ◽

Vol 17 (1) ◽

pp. 140-152 ◽

Cited By ~ 13

Author(s):

Naser Jafari ◽

James Drury ◽

Andrew J. Morris ◽

Fredrick O. Onono ◽

Payton D. Stevens ◽

...

Keyword(s):

Colorectal Cancer ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

De Novo ◽

Metastatic Potential ◽

Acid Synthesis ◽

Sphingolipid Metabolism

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Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans

Gut ◽

10.1136/gutjnl-2018-317581 ◽

2019 ◽

Vol 69 (1) ◽

pp. 177-186 ◽

Cited By ~ 20

Author(s):

Li Che ◽

Wenna Chi ◽

Yu Qiao ◽

Jie Zhang ◽

Xinhua Song ◽

...

Keyword(s):

Fatty Acid ◽

Cell Lines ◽

Knockout Mice ◽

Fatty Acid Synthase ◽

De Novo ◽

Therapeutic Option ◽

Regulatory Element ◽

Cholesterol Biosynthesis ◽

Dominant Negative ◽

Comparative Genomic

ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specificFasnknockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type andFasnknockout mice. Human HCC cell lines were used for in vitro studies.ResultsAblation ofFasnsignificantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged inFasnknockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss ofFasnpromoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis inFasnknockout mice. Similarly, silencing ofFASNresulted in increasedSREBP2activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR)expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

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Oncogene Mutations in Colorectal Polyps Identified in the Norwegian Colorectal Cancer Prevention (NORCCAP) Screening Study

Clinical Medicine Insights Pathology ◽

10.4137/cpath.s40143 ◽

2016 ◽

Vol 9 ◽

pp. CPath.S40143 ◽

Cited By ~ 8

Author(s):

Jon A. Lorentzen ◽

Krzysztof Grzyb ◽

Paula M. De Angelis ◽

Geir Hoff ◽

Tor J. Eide ◽

...

Keyword(s):

Colorectal Cancer ◽

De Novo ◽

Population Based ◽

Colorectal Polyps ◽

Braf Mutations ◽

Kras Mutations ◽

Serrated Polyps ◽

Screening Study ◽

Colorectal Cancer Prevention ◽

Mutation Spectra

Data are limited on oncogene mutation frequencies in polyps from principally asymptomatic participants of population-based colorectal cancer screening studies. In this study, DNA from 204 polyps, 5 mm or larger, were collected from 176 participants of the NORCCAP screening study and analyzed for mutations in KRAS, BRAF, and PIK3CA including the rarely studied KRAS exons 3 and 4 mutations. KRAS mutations were identified in 23.0% of the lesions and were significantly associated with tubulovillous adenomas and large size. A significantly higher frequency of KRAS mutations in females was associated with mutations in codon 12. The KRAS exon 3 and 4 mutations constituted 23.4% of the KRAS positive lesions, which is a larger proportion compared to previous observations in colorectal cancer. BRAF mutations were identified in 11.3% and were associated with serrated polyps. None of the individuals were diagnosed with de novo or recurrent colorectal cancer during the follow-up time (median 11.2 years). Revealing differences in mutation-spectra according to gender and stages in tumorigenesis might be important for optimal use of oncogenes as therapeutic targets and biomarkers.

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