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Mesenchymal tumor cells drive adaptive resistance of Trp53-/- breast tumor cells to inactivated mutant Kras

ABSTRACT: Mesenchymal tumor cells drive adaptive resistance of Trp53-/- breast tumor cells to inactivated mutant Kras

PROVIDER: PRJNA729967 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14536326_1.fastq.gz	Fastqsanger.gz
	SRR14536326_2.fastq.gz	Fastqsanger.gz
	SRR14536327_1.fastq.gz	Fastqsanger.gz
	SRR14536327_2.fastq.gz	Fastqsanger.gz
	SRR14536328_1.fastq.gz	Fastqsanger.gz

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RNA sequencing comparing mouse lung cancer cell lines derived from Kras G12D Trp53 -/- and Kras G12D Trp53 -/- sgMga tumors

Project description:The goal of this study was to compare expression profiles of mouse Kras G12D Trp53 -/- lung cancer cells that have inactivated MGA compared to controls

2020-11-17 | GSE161606 | GEO

Mesenchymal tumor cells drive adaptive resistance of Trp53-/- breast tumor cells to inactivated mutant Kras

Project description:As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D-independent tumor cells show a strong mesenchymal profile with active MAPK/ERK signaling. Both KrasG12D-dependent and KrasG12D-independent tumors display a high level of genomic instability, and KrasG12D-independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial–mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53-/- breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.

2022-04-04 | GSE174441 | GEO

Mesenchymal tumor cells drive adaptive resistance of Trp53<sup>-/-</sup> breast tumor cells to inactivated mutant Kras.

Project description:As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D , develops breast tumors. Upon inactivation of KrasG12D , tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D -independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. Both KrasG12D -dependent and KrasG12D -independent tumors display a high level of genomic instability, and KrasG12D -independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial-mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53-/- breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.

| S-EPMC9441006 | biostudies-literature

Apc, Kras, and Trp53 mutations

Project description:Apc, Kras, and Trp53 mutations

| PRJNA515706 | ENA

Wild Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell survival

Project description:Loss of Pten in the KrasG12D;Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated expression of wild type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53-) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53- OSE cells, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (an MDM2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low grade ovarian cancer cells, wild type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing type I ovarian cancer and other cancers in humans where wild-type TP53 is expressed. A direct comparison of ovarian surface epithelia cells from three different genotype mice

2012-06-20 | E-GEOD-34882 | biostudies-arrayexpress

RNA sequencing comparing in-vitro lentiviral CRISPR-Cas9 knockdown of Non-Canonical Polycomb Repressive Complex 1.6 members from a Kras G12D Trp53 -/- background mouse lung cancer cell line

Project description:The goal of this study was to compare expression profiles of mouse Kras G12D Trp53 -/- lung cancer cells that have inactivated ncPRC1.6 components to a ncPRC1.6 wild type condition

2021-06-01 | GSE175838 | GEO

Wild Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell survival

2012-06-21 | GSE34882 | GEO

Atp4b-Cre;Cdh1(fl/fl);Kras(LSL-G12D/+);Trp53(fl/fl);Rosa26(LSL-YFP/LSL-YFP) mouse stomach vs. Atp4b-Cre;Cdh1(fl/+);Kras(LSL-G12D/+);Trp53(fl/fl);Rosa26(LSL-YFP/LSL-YFP) mouse stomach microarray

Project description:We wished to investigate the role of E-cadherin loss in our mouse parietal cell/pre-parietal cell E-cadherin knock-out, p53 knock-out, oncogenic Kras induced model of gastric cancer. As such, we isolated RNA from stomach tissue from our E-cadherin knock-out model (Atp4b-Cre;Cdh1(fl/fl);Kras(LSL-G12D/+);Trp53(fl/fl);Rosa26(LSL-YFP/LSL-YFP)) and our E-cadherin heterozygous model (Atp4b-Cre;Cdh1(fl/+);Kras(LSL-G12D/+);Trp53(fl/fl);Rosa26(LSL-YFP/LSL-YFP)). We then performed a microarray on this stomach tissue from four independent mice of each genotype. Differentially expressed genes were identified and gene set overlap analysis was used to identify pathways enriched in one model over the other.

2018-05-01 | E-MTAB-5833 | biostudies-arrayexpress

RNAi off-target analysis in Trp53-/- mouse embryonic fibroblasts transduced with miRNA-based shRNAs targeting Trp53.

Project description:We analyzed miRNA-based shRNA off-target effects by transducing Trp53-/- MEFs at single- and high-copy with six well-characterized, potent and weak Trp53 shRNAs. To advance RNAi therapy for KRAS-mutant cancer, we developed a functionally validated library of siRNAs against RAS pathway genes that minimize off-target effects and enable combination gene silencing at low dose. We developed an in vivo model for real-time tracking of nanoparticle-based siRNA delivery and offer proof-of-principle that siRNA-mediated inhibition of a single gene (KRAS) or combinations of genes (A/B/C-RAF or KRAS+PIK3C-A/B) can impair the growth of KRAS-mutant colorectal cancer xenografts. Trp53-/- MEFs were transduced with LMP expressing Trp53 shRNAs at single copy (11-21% infection efficiency) and high copy (>98% infection efficiency), selected on puromycin and grown in absence of the selection agent before harvest. Uninfected Trp53-/- MEFs and Trp53-/- MEFs infected with an empty vector control served as M-bM-^@M-^\no shRNAM-bM-^@M-^] reference.

2014-08-01 | E-GEOD-59952 | biostudies-arrayexpress

RNA sequencing comparing mouse lung cancer cell lines derived from Kras G12D Trp53 -/- and Kras G12D Trp53 -/- sgMga tumors

Project description:RNA sequencing comparing mouse lung cancer cell lines derived from Kras G12D Trp53 -/- and Kras G12D Trp53 -/- sgMga tumors

| PRJNA678894 | ENA