FGF Signaling in the Self-Renewal of Colon Cancer Organoids
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PROVIDER: PRJNA487466 | ENA |
REPOSITORIES: ENA
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Project description:With their ability to self-renew and simultaneously fuel the bulk tumor mass with highly proliferative tumor cells, cancer stem cells (CSC) are supposedly driving cancer progression. However, the CSC-phenotype in colorectal cancer (CRC) is unstable and dependent on environmental cues. Since FGF2 is essential for adult and embryonic stem cell culture to maintain self-renewal, we investigated its role in advanced CRC using tumor-derived organoids as experimental model. We found that FGF-Receptor (FGFR) inhibition prevents organoid formation in very early expanding cells but induces cyst formation when applied to already established organoids. Comprehensive transcriptome analyses revealed that the induction of the transcription factor activator protein-1 (AP-1) together with a MAPK stimulation was most prominent after FGFR-inhibition. These effects resemble mechanisms of an acquired resistance against other described tyrosine kinase inhibitors such as targeted therapies against the EGF-Receptor. Furthermore, we detected elevated expression levels of several self-renewal and stemness-associated genes in organoid cultures with active FGF2 signaling. The combined data assumes that CSC are a heterogeneous subpopulation while self-renewal is a common feature regulated by many different pathways. Finally, we highlight the effects of FGF2 signaling as one of numerous aspects of the complex regulation of stemness in cancer.
2020-09-01 | GSE118949 | GEO
Project description:Esrrb is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome by mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both, the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.
2015-07-24 | PXD002183 | Pride
Project description: Not available
| S-EPMC6874569 | biostudies-literature
Project description:Both FGF and WNT pathways play important roles in embryonic development, stem cell self-renewal and are frequently deregulated in breast cancer. To study the cooperation between FGF and WNT signaling, we have generated a mouse model, MMTV-WNT1/MMTV-iFGFR1 (WNT/iR1), in which we could chemically overactivate iFGFR1 in a ligand-independent manner.
2017-11-22 | MSV000081730 | MassIVE
Project description:MiRNAs have been identfied to play an important role in cancer stem cells. MiR23b is differentially expressed in various forms of cancer including colorectal cancer as compared to their normal counterparts. MiR23b regulates various aspects of cell behaviour such as differentiation, apoptosis and motility. The goal of the study was to identify the novel role of miR23b in self-renewal property of colon cancer stem cells via regulation of its candidate target mRNAs. To address this aim, HT29 colon cancer cells were transfected with miR23b Precursor, Antimir and their respective controls. RNA SEQ analysis of the cells with altered levels of miR23b assisted in the identification of interesting mRNA targets influenced by miR23b expression and involved self-renewal pathways. HT29 cells with altered levels of miR23b was subjected to RNA SEQ analysis to identify differential expresssion of mRNA targets of mIR23b
2015-02-28 | E-GEOD-59290 | biostudies-arrayexpress
Project description:MiRNAs have been identfied to play an important role in cancer stem cells. MiR23b is differentially expressed in various forms of cancer including colorectal cancer as compared to their normal counterparts. MiR23b regulates various aspects of cell behaviour such as differentiation, apoptosis and motility. The goal of the study was to identify the novel role of miR23b in self-renewal property of colon cancer stem cells via regulation of its candidate target mRNAs. To address this aim, HT29 colon cancer cells were transfected with miR23b Precursor, Antimir and their respective controls. RNA SEQ analysis of the cells with altered levels of miR23b assisted in the identification of interesting mRNA targets influenced by miR23b expression and involved self-renewal pathways.
2015-02-28 | GSE59290 | GEO
Project description:Aberrant activation of WNT signaling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumor stem cell phenotype and identify the zinc-finger transcription factor GATA6 as key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells while it restricts BMP signaling to differentiated tumor cells. Genetic deletion of Gata6 in mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumor stem cells. In human tumors, GATA6 represses BMP4 gene expression through binding to a regulatory region that has been previously linked to increased susceptibility to develop CRC. Thus, GATA6 creates a permissive environment for tumor stem cell expansion by controlling the major signaling pathways that influence CRC initiation. Total RNA from biological replicates of VillinCreERT2Gata6+/+Apcfl/fl and VillinCreERT2Gata6fl/flApcfl/fl colon adenoma tumor organoids grown for one week in control media (see growth protocol).Total RNA was extracted using the TRIzolM-BM-. Plus RNA Purification Kit (Life Technologies).
2014-06-19 | E-GEOD-49479 | biostudies-arrayexpress
Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)
2010-12-22 | E-GEOD-25334 | biostudies-arrayexpress
Project description:Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of Trophoblast Stem Cells
| PRJEB9375 | ENA
Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation.
2010-12-22 | GSE25334 | GEO