RET activation controlled by MAB21L4-CacyBP interaction in squamous cell carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788908 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17283423_1.fastq.gz | Fastqsanger.gz | |||
| SRR17283423_2.fastq.gz | Fastqsanger.gz | |||
| SRR17283424_1.fastq.gz | Fastqsanger.gz | |||
| SRR17283424_2.fastq.gz | Fastqsanger.gz | |||
| SRR17283425_1.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2022-06-24 | GSE190907 | GEO
Project description:For most multigenic disorders, clinical manifestation (penetrance) and presentation (expressivity) are likely to be an outcome of genetic interaction between multiple susceptibility genes. Here, using gene knockouts in mice we evaluated genetic interaction between loss of Ret and loss of Sema3d, two Hirschsprung disease (HSCR) susceptibility genes. We intercrossed Ret and Sema3d double null heterozygotes to generate mice with the nine possible genotypes and assessed survival by counting various genotypes, myenteric plexus development by acetylcholinesterase (AchE) staining and embryonic day 12.5 (E12.5) gut transcriptome by RNA-sequencing. Survival rates of Ret wildtype, null heterozygote and null homozygote mice at E12.5, birth and weaning were not influenced by the genotypes at Sema3d locus and vice-versa. Loss of myenteric plexus was observed only in all Ret null homozygotes, irrespective of the genotypes at Sema3d locus, and Sema3d null heterozygote and homozygote mice had normal gut innervation. As compared to wildtype mice gut gene expression, loss of Ret in null homozygotes led to differential expression of ~300 genes, whereas loss of Sema3d in null homozygotes had no major consequence and there was no evidence supporting major interaction between the two genes influencing gut transcriptome. Overall, given the null alleles and phenotypic assays used, we did not find evidence for genetic interaction between Ret and Sema3d affecting survival, myenteric plexus formation or gut transcriptome.
2017-03-28 | GSE89627 | GEO
Project description:Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC.SignificanceDownregulation of RET mediated by MAB21L4-CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.
| S-EPMC9444977 | biostudies-literature
Project description:RET-aberrant cancer discovered as a relevant targetable oncogene in several types of tumors, whose inhibitors have marked efficacy. However, some of patients with RET-aberrant cancer are insensitive to RET- tyrosine kinase inhibitors (TKIs) and are clinically non-responders. Recently, drug-tolerant mechanisms have been gaining attention as targets for initial therapies aimed at overcoming drug resistance. However, the underlying mechanisms of drug-tolerant cells emergence treated with RET-TKIs derived from RET-aberrant cancer cells remains unknown. In this study, HER3 signal activity through YAP1 was led to maintaining cell survival and inducing the emergence of cells tolerant to RET-TKIs selpercatinib and pralsetinib in high YAP1 expressed RET- rearranged cancer cells. These results suggested that YAP1-HER3 axis plays pivotal roles for cell survival under an exposure with RET-TKIs in the intrinsic resistance to RET-TKIs and the emergence of tolerant cells by RET-TKIs in YAP1 expressed RET-aberrant cancer, suggesting that YAP1/HER3 inhibition and RET-TKIs is a highly potent combination for initial treatment.
2024-09-30 | GSE261830 | GEO
Project description:Endocrine therapy is the main therapeutic option for patients with estrogen receptor alpha positive (ER+) breast cancer. Nevertheless, most of them become estrogen-independent and relapse after the treatment. Ret is a tyrosine kinase receptor that shows elevated expression levels in ER+ human breast tumors. In this study, we demonstrate that activation of the Ret receptor promotes proliferation as well as cell migration irrespective of endocrine therapy. Microarray data show that Ret activation involves changes in the expression of inflammatory- and motility-related genes. In vivo treatment with a Ret pathway inhibitor in a ER+/Ret+ mouse mammary cancer model, reduces tumor growth and lung metastasis even after endocrine therapy. Additionally, we show a connection between Ret and inflammatory pathways. The pro-inflamatory cytokine IL6 lies at the core of this regulation, which involves a positive feedback loop with IL6 and the Ret pathway reciprocally stimulating each other to further leading metastasis risk. Our findings provide insight into endocrine resistance mechanism and point at the Ret pathway as a potential target for future therapies. In order to model letrozole-sensitive breast cancer we use aromatase expressing MCF7 cells (MCF7/Aro). Six-day treatment (6 days) of cultures with letrozole (L) or fulvestrant (F) reversed the proliferative effects of the exposure to the estrogen (E2) precursor androstenedione (D4A). The addition of only EtOH (E) to the cells was used as control condition of deprivation. Treatment with the Ret ligand GDNF (G) partially rescues the inhibition of estrogen-dependent proliferation in these cells. To go deeper insight into the pathways involved, we decided to perform a microarray following different treatments (1-8: E, E+G, D, D+G, L, L+G, F, F+G) used in proliferation assays. Three biological replicates (rep 1-3) were used to the array.
2013-09-25 | E-GEOD-41405 | biostudies-arrayexpress
Project description:Endocrine therapy is the main therapeutic option for patients with estrogen receptor alpha positive (ER+) breast cancer. Nevertheless, most of them become estrogen-independent and relapse after the treatment. Ret is a tyrosine kinase receptor that shows elevated expression levels in ER+ human breast tumors. In this study, we demonstrate that activation of the Ret receptor promotes proliferation as well as cell migration irrespective of endocrine therapy. Microarray data show that Ret activation involves changes in the expression of inflammatory- and motility-related genes. In vivo treatment with a Ret pathway inhibitor in a ER+/Ret+ mouse mammary cancer model, reduces tumor growth and lung metastasis even after endocrine therapy. Additionally, we show a connection between Ret and inflammatory pathways. The pro-inflamatory cytokine IL6 lies at the core of this regulation, which involves a positive feedback loop with IL6 and the Ret pathway reciprocally stimulating each other to further leading metastasis risk. Our findings provide insight into endocrine resistance mechanism and point at the Ret pathway as a potential target for future therapies.
2013-09-25 | GSE41405 | GEO
Project description:Quantitative proteomic profiling the lung squamous carcinoma cells
2016-07-14 | MSV000079911 | MassIVE
Project description:Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from point mutations or chimaeric fusion genes, such as BCR ABL1 or JAK2 V617F. We report here for the first time in hematological malignancies, two novel fusion genes involving the TK RET, BCR-RET and FGFR1OP-RET, in chronic myelo monocytic leukemia (CMML) cases. The two RET fusion genes lead to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. We also report that the BCR-RET fusion protein is insensitive to Imatinib but sensitive to Sorafenib in vivo. CMML is an hematopoietic malignancy associated with the frequent activation of the RAS pathway. The RET fusion genes seems to constitutively mimic the same signaling pathway than RAS mutations. Overall, the RET fusion genes behaviors in the monocytic lineage underlie the role of the normal RET TK activity during the physiological monocytic differentiation. We analysed BAF/3 cells infected by BCR-RET, FGFR1OP-RET or BCR-ABL1P210 fusion genes retroviruses and sorted out using EGFP fluorescence, with Affymetrix GeneChip MouseGene 1.0 ST platform.
2012-01-06 | E-GEOD-34900 | biostudies-arrayexpress
Project description:Aberrant activation of Anaplastic Lymphoma Kinase (ALK) drives neuroblastoma (NB). Previous work has identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK driven gene signature in NB. To further address the role of RET in NB, RET knock-out (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MET RTKs as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.
2021-09-10 | PXD024551 | Pride
Project description:NRF2 activation in TRP53:P16 deficient mice drives oral squamous cell carcinoma
2024-01-31 | PXD048887 | Pride