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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jan 24, 2024 |
| Title |
Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [DSP] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| 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.
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| Overall design |
Digital spatial profiling (DSP) was performed on tumor tissues that were derived from AKB6 xenografts developed in C57BL/6 strain. Mice were treated with vehicle and MRTX1133 (30 mg/kg) once a day via IP administration. The DSP analysis was performed on vehiclle (n=2) and MRTX1133 treated (n=4) tissues. A total of 6 ROIs were selected from vehicle treted tissues and 23 ROIs were selected from MRTX1133 treated tissues.
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| 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 |
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| Submission date |
Dec 06, 2023 |
| Last update date |
Apr 25, 2024 |
| Contact name |
Jianxin Wang |
| Organization name |
Roswell Park Comprehensive Cancer Center
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| Department |
Molecular and Cellular Biology
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| Street address |
665 Elm Street
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| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14203 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (23)
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| GSM7949456 |
AKB6, Vehicle, ROI 004 |
| GSM7949457 |
AKB6, Vehicle, ROI 005 |
| GSM7949458 |
AKB6, Vehicle, ROI 006 |
| GSM7949459 |
AKB6, MRTX1133, ROI 001 |
| GSM7949460 |
AKB6, MRTX1133, ROI 003 |
| GSM7949461 |
AKB6, MRTX1133, ROI 004 |
| GSM7949462 |
AKB6, MRTX1133, ROI 005 |
| GSM7949463 |
AKB6, MRTX1133, ROI 006 |
| GSM7949464 |
AKB6, MRTX1133, ROI 007 |
| GSM7949465 |
AKB6, MRTX1133, ROI 008 |
| GSM7949466 |
AKB6, MRTX1133, ROI 009 |
| GSM7949467 |
AKB6, MRTX1133, ROI 010 |
| GSM7949468 |
AKB6, MRTX1133, ROI 011 |
| GSM7949469 |
AKB6, MRTX1133, ROI 012 |
| GSM7949470 |
AKB6, MRTX1133, ROI 014 |
| GSM7949471 |
AKB6, MRTX1133, ROI 015 |
| GSM7949472 |
AKB6, MRTX1133, ROI 016 |
| GSM7949473 |
AKB6, MRTX1133, ROI 018 |
| GSM7949474 |
AKB6, MRTX1133, ROI 019 |
| GSM7949475 |
AKB6, MRTX1133, ROI 023 |
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| This SubSeries is part of SuperSeries: |
| GSE249541 |
Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models. |
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| Relations |
| BioProject |
PRJNA1049456 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE249538_Mm_R_NGS_WTA_v1.0.pkc.gz |
1.8 Mb |
(ftp)(http) |
PKC |
| GSE249538_RAW.tar |
1.6 Mb |
(http)(custom) |
TAR (of DCC) |
| GSE249538_Sample_Annotation.xlsx |
11.4 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
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