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PROX1 mediates chemoresistance-associated recurrence via maintenance of quiescent colon cancer stem cells

ABSTRACT: PROX1 mediates chemoresistance-associated recurrence via maintenance of quiescent colon cancer stem cells

PROVIDER: PRJNA592447 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10559800.fastq.gz	Fastqsanger.gz
	SRR10559801.fastq.gz	Fastqsanger.gz
	SRR10559802.fastq.gz	Fastqsanger.gz
	SRR10559803.fastq.gz	Fastqsanger.gz
	SRR10559804.fastq.gz	Fastqsanger.gz

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PROX1 mediates chemoresistance-associated recurrence via maintenance of quiescent colon cancer stem cells

Project description:Cancer stem cells (CSCs) are profoundly associated with refractory nature of cancer. A quiescent population of CSCs is responsible for tumorigenesis and chemoresistance in leukemia, whereas neither the presence nor clinical importance of the quiescent CSCs is clearly established in solid tumors. In colon cancer, LGR5 is regarded as a functional marker of CSCs, but heterogeneity among LGR5+ cells was not clearly defined. Here we stratified LGR5+ cells by single-cell gene expression analyses and revealed that a tumorigenic population of mouse LGR5+ cells resides in a quiescent state. We identified 23 signature genes that were uniquely expressed in the quiescent CSCs of mouse tumors, and found that 7 of them were also specifically expressed in a quiescent population of LGR5+ cells in human colon xenograft tumors. Among them, PROX1 was expressed in invasive fronts of colon tumors. PROX1 was induced by TCF1 (TCF7), and the TCF1-mediated PROX1 expression was responsible for not only the maintenance of quiescence but also chemoresistance of colon cancer organoids. Knockout of PROX1 in patient-derived xenograft tumors resulted in inhibition of tumor recurrence after chemotherapeutic treatment. Our data underscore the therapeutic importance of a quiescent CSC population in colon cancer.

2019-11-30 | GSE141157 | GEO

RNAi knock down using siRNAs targeting PROX1 or GFP in human colon carcinoma cells

Project description:siRNA transfection using either two different siRNAs targeting PROX1 or GFP

2008-09-03 | E-MEXP-1422 | biostudies-arrayexpress

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells [BMDMs]

Project description:Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown. We induced chemoresistant and quiescent (G0) leukemic cells by serum-starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the up-regulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα—prior to or along with chemotherapy—substantially reduced chemoresistance in primary leukemic cells ex vivo and in vivo. These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE bearing mRNAs that promote chemoresistance. By disrupting this pathway, we developed an effective combination therapy against chemosurvival.

2020-01-06 | GSE141075 | GEO

Comparison of Prox1 expressing and Prox1 knockout intestinal tumors and the effect of A2V+CD40

Project description:Control or A2V+CD40 treated Prox1-proficient (AP) and Prox1-deficient (APP) tumors

2020-02-04 | GSE124716 | GEO

RNA-seq analyses of doxycycline-induced PROX1-exprressing cells in human colon cancer spheroids

Project description:We performed RNA-seq analyses of the human cancer spheroids expressing PROX1 induced by doxycycline treatment.

2023-04-23 | GSE193937 | GEO

RNAi knock down using siRNAs targeting PROX1 or Â§-catenin in human colon carcinoma cells

Project description:PROX1 or §-catenin was depleted in SW480 by siRNA transfection and the gene expression profiles were compared to negative controls to study the genes affected.

2018-03-01 | E-MTAB-717 | biostudies-arrayexpress

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells [Human cell lines]

2020-01-06 | GSE141329 | GEO

Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

Project description:Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells. Microrrays were used to identify gene expression profiles and pathways that are differentially activated after enforced expression of PROX1 in the PROX1-negative human pancreatic ductal adenocarcinoma (PDAC) cell line Capan1. MSCV retroviral transduction was used to generate Capan1 cells that ectopically express PROX1 and selected for puromycin resistance. Three independent transductions with control virus (MSCV_puro) and 3 independent transductions with Prox1-cDNA virus (MSCV_PROX1_puro) were conducted for these experiments.

2016-02-11 | E-GEOD-58547 | biostudies-arrayexpress

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Project description:Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for adynamic regulation of numerous processes including transcriptional reprograming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation became less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet led to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the preservation of metabolic health.

2023-10-24 | PXD041329 | Pride

Quiescent human glioblastoma cancer stem cells mediate tumor initiation, expansion, and recurrence following chemotherapy

Project description:Quiescent human glioblastoma cancer stem cells mediate tumor initiation, expansion, and recurrence following chemotherapy

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