PROX1 mediates chemoresistance-associated recurrence via maintenance of quiescent colon cancer stem cells
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PROVIDER: PRJNA592447 | ENA |
REPOSITORIES: ENA
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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
Project description:There is increasing evidence that cancer recurrence and resistance to chemotherapy are linked to a subset of cancer stem cells. However, detecting these cells specifically and targeting them therapeutically remain challenging. As microRNAs (miRNAs) are emerging as key players in cancer biology, we set up to identify miRNAs involved in chemoresistance of breast cancer stem cells. In this study, we enriched populations of chemoresistant cancer stem cells from breast cancer and non-transformed breast cell lines using mammospheres. These mammospheres were treated or not with two chemoreagents, and we profiled surviving cells using miRNA microarray analysis. Comparison of the profiles from treated and untreated mammospheres as well as control and cancer cells yielded a six-miRNAs signature specific for chemoresistant stem cell-enriched subpopulations. From this signature miR-363-3p was found to be most highly overexpressed in various breast cancer cell lines and derived cancer stem cell-enriched populations, whereas non-tumorigenic cells had low levels. Inhibition of miR-363-3p was found to decrease cancer stem cell maintenance and tumorigenicity in vitro. Consistently, miR-363-3p downregulation decreased tumor growth and metastatization by human tumor cells transplanted in mice. Finally, miR363-3p levels in the sera of 38 breast cancer patients enrolled in a neoadjuvant trial correlated well with the response to the chemotherapeutic treatments. Altogether, miR363-3p was identified as a mediator of the breast cancer stem cell phenotype, and it may provide a predictor of the response to chemotherapy from a simple blood test, as well as a potential therapeutic approach for cancer stem cell targeting. This data set aims at identifying differentially expressed miRNAs in chemoresistant mammospheres, by the profiling of miRNA in MCF7 breast cancer cell-derived mammospheres selected to be resistant to 5 Fluorouracil (5FU) or Paclitaxel, as compared to unselected MCF7 mammospheres.
2020-01-13 | GSE93710 | GEO
Project description:Control or A2V+CD40 treated Prox1-proficient (AP) and Prox1-deficient (APP) tumors
2020-02-04 | GSE124716 | GEO
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
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 | GSE141329 | GEO
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
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
Project description:Quiescent human glioblastoma cancer stem cells mediate tumor initiation, expansion, and recurrence following chemotherapy
| PRJNA785966 | ENA
Project description:Human thyroid cancer cell line BCPAP was engineered for doxycyclin-mediated inducible expressoin of Prox1 and next generation sequcing was performed to study the transcriptional regulation by Prox1 BCPAP cells were infected with rTTA2 lentivirus. The resulting cell populations were then stably transfected either with pIRES-hygromycin vector (Clontech) to generate BCPAP-Ctr cells, or with Flag-PROX1-IRES-hygromycin vector to generate BCPAP-Prx cells. PROX1 expression was induced or not in BCPAP-Ctr and BCPAP-Prx cells with 0.5 µg/ml doxycycline (Dox) for 48 hours and the total RNA samples were collected for sequencing.
2016-03-02 | E-GEOD-75059 | biostudies-arrayexpress
Project description:During central nervous system (CNS) development, proper and timely induction of axon elongation is critical for generating functional, mature neurons and neuronal networks. Despite the wealth of information on the action of extracellular cues, little is known about the intrinsic gene regulatory factors that control this developmental decision. Here we report the identification of Prox1, a homeobox transcription factor, as a key player in inhibiting axon elongation. Although Prox1 promotes acquisition of early neuronal identity and is expressed in nascent post-mitotic neurons, it is heavily down-regulated in the majority of terminally differentiated neurons, indicating a regulatory role in delaying axon outgrowth in newly formed neurons. Consistently, we show that Prox1 is sufficient to inhibit neurite extension in neuroblastoma cell lines. Furthermore, shRNA-mediated knock-down of Prox1 in Neuro2A cells induces the extension of neurites. More importantly, Prox1 overexpression suppresses axon elongation in primary neuronal cultures as well as in the developing mouse brain, while Prox1 knock-down promotes axon outgrowth. Mechanistically, RNA-Seq analysis reveals that Prox1 affects critical pathways for neuronal maturation and neurite extension. Interestingly, Prox1 strongly inhibits many components of Ca2+ signaling pathway, an important mediator of axon extension and neuronal maturation. In accordance, Prox1 represses Ca2+ entry upon KCl-mediated depolarization and reduce CREB phosphorylation. These observations suggest that Prox1 acts as a potent suppressor of axon elongation by inhibiting Ca2+ signaling pathway. This action may provide the appropriate time window for nascent neurons to find the correct position in the CNS prior to initiation of axon elongation.
2020-12-31 | GSE158904 | GEO