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Series GSE249539 Query DataSets for GSE249539
Status Public on Jan 24, 2024
Title Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [RNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here, we assessed the cellular response to pharmacological KRAS inhibition, targeting the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of the KRASG12D allele with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR-Cas9 loss-of-function screens identified ITGB1 as a novel driver for enhanced therapeutic response that regulates mechanotransdcution signaling and YAP/TAZ expression, which is further confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures. Moreover, MRTX1133 elicits a more pronounced cytostatic effect in controlling the in vivo tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition leads to potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133-mediated KRAS inhibition enhances interferon-γ signaling and induces antigen presentation that modulates the tumor microenvironment. Further investigation on the immunological response using single-cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8+ T-cells. Thus, both tumor cell-intrinsic and extrinsic events contribute to response and credential KRASG12D inhibition as a promising strategy for a large percentage of PDAC tumors.
 
Overall design Patient derived PDAC cell lines, 1222 and 3226 were seeded in 6 well dish at a denisty of 100,000 cells/well. Following 24 hours, the cells were treated with 0.1% DMSO and MRTX1133 (500 nM). The tretments were done in triplicates. The cells were exposed to the MRTX1133 for 48 hours and RNA was extracted using Quiagen RNeasy plus kit.
 
Contributor(s) Kumarasamy V, Wang J, Frangou C, Wan Y, Dynka A, Rosenheck H, Dey P, Abel EV, Knudsen ES, Witkiewicz AK
Citation(s) 38294344
Submission date Dec 06, 2023
Last update date Apr 25, 2024
Contact name Erik Knudsen
E-mail(s) Erik.Knudsen@RoswellPark.org
Organization name Roswell Park Comprehensive Cancer Center
Department Molecular and Cellular Biology
Street address 665 Elm Street
City Buffalo
State/province NY
ZIP/Postal code 14203
Country USA
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (12)
GSM7949476 1222, Control, bio rep 1
GSM7949477 1222, Control, bio rep 2
GSM7949478 1222, Control, bio rep 3
This SubSeries is part of SuperSeries:
GSE249541 Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models.
Relations
BioProject PRJNA1049461

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE249539_RAW.tar 14.8 Mb (http)(custom) TAR (of RESULTS)
SRA Run SelectorHelp
Raw data are available in SRA

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