Degree of Tissue Differentiation Dictates Susceptibility to BRAF-driven Colorectal Cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE106330 | GEO | 2017/12/26
SECONDARY ACCESSION(S): PRJNA416320
REPOSITORIES: GEO
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Project description:BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
2023-09-07 | GSE234372 | GEO
Project description:BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
2023-09-27 | GSE236515 | GEO
Project description:In spite of the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.
2023-08-29 | PXD042499 | Pride
Project description:It is not known why cancers arising in anatomically distinct locations but within the same tissue type can exhibit stark differences in molecular, pathological and clinical features. Cancers arising in proximal and distal sites of the colon are emblematic of these above differences as the proximal and distal colon cancers harbor differences in key molecular features, with BRAFV600E oncogene predominantly occurring in proximal colon cancers in the context of the increased promoter DNA methylation phenotype (CIMP-high), while distal colon cancers lack these molecular features. We determined the molecular basis of tissue-location specificity of driver mutations using normal mouse derived organoid models for colon cancer initiation. We show that the homeobox transcription factor, Cdx2, which is downregulated by DNA methylation in proximal colon cancers, plays distinct roles in regulating stem cell and differentiation in proximal compared to distal colon stem cells. Loss of Cdx2 altered the differentiation and stem cell programs and result in transformation by BRAFV600E specifically in the proximal but not distal colon stem cells. Analyses of RNA expression and Cdx2-binding to target genomic regions revealed that Cdx2 was a key effector of the transcriptional response to differentiation cues in proximal colon cells. This proximal colon-specific transcriptional program concurrently is tumor suppressive, and its loss sufficiently creates permissive state for oncogenic-BRAF mutations. The transcriptional program associated with Cdx2 loss in mouse proximal organoids matches that of human proximal colon cancers with downregulated CDX2 expression due to epigenetic silencing. Our analyses reveal that developmental and lineage-restricted transcription factors maintain tissue-location specific transcriptional programs which create critical dependencies for tumor initiation.
2023-12-12 | GSE218479 | GEO
Project description:It is not known why cancers arising in anatomically distinct locations but within the same tissue type can exhibit stark differences in molecular, pathological and clinical features. Cancers arising in proximal and distal sites of the colon are emblematic of these above differences as the proximal and distal colon cancers harbor differences in key molecular features, with BRAFV600E oncogene predominantly occurring in proximal colon cancers in the context of the increased promoter DNA methylation phenotype (CIMP-high), while distal colon cancers lack these molecular features. We determined the molecular basis of tissue-location specificity of driver mutations using normal mouse derived organoid models for colon cancer initiation. We show that the homeobox transcription factor, Cdx2, which is downregulated by DNA methylation in proximal colon cancers, plays distinct roles in regulating stem cell and differentiation in proximal compared to distal colon stem cells. Loss of Cdx2 altered the differentiation and stem cell programs and result in transformation by BRAFV600E specifically in the proximal but not distal colon stem cells. Analyses of RNA expression and Cdx2-binding to target genomic regions revealed that Cdx2 was a key effector of the transcriptional response to differentiation cues in proximal colon cells. This proximal colon-specific transcriptional program concurrently is tumor suppressive, and its loss sufficiently creates permissive state for oncogenic-BRAF mutations. The transcriptional program associated with Cdx2 loss in mouse proximal organoids matches that of human proximal colon cancers with downregulated CDX2 expression due to epigenetic silencing. Our analyses reveal that developmental and lineage-restricted transcription factors maintain tissue-location specific transcriptional programs which create critical dependencies for tumor initiation.
2023-12-12 | GSE218480 | GEO
Project description:Most cancer genomics papers to date have focused on aberrations in genomic DNA and protein-coding transcripts. However, around 50% of transcripts have no coding potential and may exist as non-coding RNA. We performed RNA-seq in BRAFv600e melanoma skin cancer and on melanocytes over-expressing oncogenic BRAF to catalog transcriptome remodeling. We discovered that BRAF regulates expression of 1027 protein coding transcripts, 39 annotated lncRNAs and 70 novel transcripts. Many of the novel transcripts are lncRNAs. We used an indepenedent dataset to interrogate our novel transcripts and found that the novel lncRNA BANCR is a BRAF-regulated lncRNA recurrently upregulated in melanoma. Knockdown of BANCR impairs melanoma cell migration. Whole transcriptome RNA-seq followed assembly to Refseq/Gencode and de novo transcript assembly. RNA-seq performed on: 2 BRAFv600e melanomas, melanocytes+RFP control and melanocytes + BRAFv600e. We discovered protein-coding transcripts, annotated ncRNAs and novel transcripts (including lncRNAs) regulated by BRAFv600e also coordinately expressed in melanoma.
2012-04-28 | E-GEOD-33092 | biostudies-arrayexpress
Project description:Degree of Tissue Differentiation Dictates Susceptibility to BRAF-driven Colorectal Cancer
| PRJNA416320 | ENA
Project description:Objective: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases, and includes tumours that are amongst the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen activated kinase (MAPK) pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype (CIMP), leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein. Design: We utilise organoid culture combined with CRISPR/Cas9 genome engineering, to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair. Results: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting. Conclusion: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.
2018-04-30 | GSE112774 | GEO
Project description:The oncogenic mutation BRAFV600E is a common event in nevi and melanomas, which are aggressive skin tumors characterized by MAPK signaling pathway activation. It has been observed that mutated benign melanocytic lesions can remain unchanged for decades, but also proliferate or undergo oncogene-induced senescence. The purpose of this study was to investigate the presence of a gene expression signature in BRAFV600E mutated nevi compared to wild-type ones, all derived from sun exposed sites. Microdissected tissues from excisional biopsies of acquired nevi were analyzed to detect the presence of BRAF and NRAS mutations and to profile whole genome expression by means of oligonucleotide microarrays. BRAFV600E mutation was evidenced in 64% of nevi, while no NRAS mutations were detected. Functional analysis of genes differentially expressed between wild-type and mutated lesions pointed out the role of oxidative stress in causing the oncogenic BRAF mutation and that the direct consequence of constitutive activation of BRAF-MEK-ERK pathway, in a benign contest, is the activation of apoptosis, autophagy and senescence. Our data also indicate that in mutated lesions, p53 plays a crucial role in the maintenance of the benign status. In our study, in order to understand the role of BRAF mutation in acquired nevi, we performed gene expression profiling analysis on fourteen lesions derived from intermittently exposed sites, using whole genome oligonucleotide microarrays. Expression data were coupled with sequencing results on BRAF and NRAS genes and class comparison algorithms were applied to detect sequences differentially expressed between BRAFV600E and BRAFwt-NRASwt lesions. Some of the obtained results were further validated by Real-Time RT-PCR on an independent cohort of samples. Mutation analysis evidenced BRAF mutations in 64% of the common acquired nevi. All the mutations consisted in the substitution V600E (T1799A). No alteration was found on exon 11 of the BRAF gene nor on exons 1 and 2 of the NRAS gene, as expected since no lesion came from chronically exposed sites. Transcriptome analysis was carried out using oligo-microarrays and differential expression was tested applying the Linear Models package LIMMA available at www.bioconductor.org that uses Bayesian statistics to compute the probability of a gene being differentially expressed. Only 25 transcripts had B value greater then 2. We then performed a one-way ANOVA, dividing samples into three classes according to their BRAF mutational status (wt, ++, +++) as assessed by pyrosequencing. We found 2882 known transcripts by selecting those with ANOVA p-value<0.01 and increasing or decreasing expression trends along the three classes. Functional analysis was performed using the MetaCoreTM software package to identify overrepresented functional processes. BRAF signature, acquired nevi, gene expression profiling "++ and +++" refer to the percentage of alleles carrying the mutation in the *BRAF*V600E lesions. This has been assessed by pyrosequencing analysis (Venesio et al, 2008. PMID= 18408659).
2016-06-30 | E-GEOD-23976 | biostudies-arrayexpress
Project description:Abnormal promoter DNA hypermethylation arises early during tumorigenesis and yet its role in cancer initiation has remained underexplored. An important scenario for examining this is, BRAFV600E-mutant colon adenocarcinomas (COAD) which most often arise in the proximal colon and harbor extensive, abnormal gene promoter CpG-island methylation or the methylator phenotype (CIMP). How CIMP and BRAF-mutations specifically interact for COAD initiation has remained unclear. Using mouse colon-derived organoids, we show promoter hypermethylation spontaneously arises in wild type cells mimicking “aging like” phenotype. The silenced genes sufficiently activate the Wnt pathway, causing a stem–like state and profound differentiation block. This phenotype renders long-term cultured organoids to be rapidly susceptible to transformation by BRAFV600E with features of typical right-sided COAD. Our studies tightly link epigenetic abnormalities, suggested to arise with aging, to intestinal cell fate changes and define an “epi-driver” role for multiple abnormally silenced genes that predispose to BRAFV600E-driven colon tumorigenesis.
2019-01-01 | GSE121672 | GEO