Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with combined SOS1 and MEK Inhibition for Improved Immunotherapy Response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1103078 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28763406_1.fastq.gz | Fastqsanger.gz | |||
| SRR28763406_2.fastq.gz | Fastqsanger.gz | |||
| SRR28763407_1.fastq.gz | Fastqsanger.gz | |||
| SRR28763407_2.fastq.gz | Fastqsanger.gz | |||
| SRR28763408_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 42 |
Similar Datasets
Project description:KRAS inhibitors have demonstrated exciting pre-clinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KRASG12D, p53 mutant, murine PDAC-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intra-tumoral CD8+ T cells without durable responses. scRNA-sequencing revealed an increase in inflammatory cancer associated fibroblasts (iCAFs), M2 macrophages, and a decreased dendritic cell quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor free mice with established immune memory. Our data suggests that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
2024-04-22 | GSE264527 | GEO
Project description:KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.
2020-08-20 | GSE128385 | GEO
Project description:Expression profiling of androgen and insulin pathway regulating genes unveils SOS 1 as candidate gene for idiopathic hirsutism Background: Idiopathic Hirsutism (IH), defined as the presence of terminal hairs in females in a male-like pattern, affecting about 5% -15% of women, may result from the interaction between the androgen level and the sensitivity of the hair follicle to the androgen. The pathophysiology of IH is presumed to be linked to increased SRD5A activity, probably both isoenzyme types (SRD5A1 and SRD5A2) and generally related to an alteration in androgen receptor (AR) function. IH is often associated to metabolic syndrome, visceral obesity, dyslipidemia, insulin resistance, and hypertension.Methodology/Principal Findings: With the aim of identifying genes involved in the pathogenesis of this disorder, we investigated the expression profile of 190 genes involved in the androgen biosynthesis and metabolism, and other genes coding for products active in the insulin pathway in skin genital fibroblasts. For this purpose we selected from a cohort of 240 women affected with androgen excess syndrome a group of 52 idiopathic hirsute patients (22%) and we selected 8 of them with the higher grade of hirsutism (Ferriman & Gallway score >20) for the genetic studies comparing the data with 4 healthy women used as controls. The array gene signature in the IH patients identified 4 differentially expressed genes, 2 up-regulated and 2 down-regulated (FC≥± 1.5). Differentially expressed genes included products involved in insulin signalling while no androgens related genes were found altered in expression levels. We found that one of the over expressed transcript codes for the SOS1 gene product, which is overproduced in IH patients compared to controls. We did not identified any genomic variants or SNPs in the SOS1 promoter region and/or witin the 3’UTR with documented functional effects on SOS1 gene expression, although some variants in the 3’UTR seems to be potentially active in modulating the binding of transcription factors. Conclusions/Significance: In the cohort of women with androgen excess syndrome studied the 22% had neither hyperandrogenemia nor biochemical sign of hyperinsulinemia. We were able to demonstrate that SOS1 mRNA is over-expressed resulting in over production of SOS1 protein in IH patients. This suggests that an increase of SOS1 protein production could reflect a situation with an increased SOS1 activity function in hirsute patients. These findings propose a role for SOS1, in cooperation with other insulin pathway genes, in the pathogenesis of IH.
2010-04-15 | GSE18022 | GEO
Project description:Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation.
2021-01-07 | PXD018296 | Pride
Project description:Sos1 and Sos2 are guanine-nucleotide exchange factors for Ras and Rac small GTPases, which are involved in a wide range of cellular responses including proliferation and migration. We have previously shown that Sos1 and Sos2 have different effects on cell migration, but the underlying mechanisms are not clear. Here, we examined the role of Sos1 and Sos2 in the overall transcriptional profile of mouse primary fibroblasts in order to unveil the specific functions of these Ras/Rac activators in regulating migration. We used microarrays to detail the impact of Sos1/2 depletion (individual or combined) in the transcriptional signature of mouse primary keratinocytes
2024-09-23 | GSE277505 | GEO
Project description:The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRASG12D). One of the most commonly used models involves targeted insertion of a cre-recombinase into the Ptf1a gene. However, this approach disrupts the Ptf1a gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRASG12D). This study aims to determine if Ptf1a haploinsufficiency affected the acinar cell response to KRASG12D before and after induction of pancreatic injury. Taken together, our results suggest Ptf1a haploinsufficiency in Ptf1acreERT mouse models promotes KRASG12D priming of genes for promotion of PDAC.
2024-08-20 | GSE252884 | GEO
Project description:Transcriptional profiling of mouse Pancreatic cancer cells comparing Pdx1-Cre LSL-KrasG12D TGIF1L/L P53L/L cells with Pdx1-Cre LSL-KrasG12D P53L/L cells, and to determine the effects of TGIF1 deletion on PDAC gene expression.
2018-01-22 | GSE108843 | GEO
Project description:Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can reveal unexpected synthetic lethal interactions and uncover biomarkers of drug sensitivity. Preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice showed that the MEK inhibitor PD0325901 (PD901) extended survival while the pan-phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 was ineffective. One outlier PD901-treated AML had a four-fold improvement in survival, and exhibited intrinsic drug resistance at relapse. This resistant leukemia arose from an evolutionary precursor of the dominant drug-sensitive AML, and KrasG12D was duplicated in both AML clones. Loss of wild-type (WT) Kras both enhanced the competitive fitness of the dominant clone and rendered it more sensitive to MEK inhibition. Similarly, colorectal cancer cell lines with loss of WT KRAS are more sensitive to MEK inhibitors, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized a heterozygous mutant HCT116 cells to drug treatment. In a large prospectively characterized cohort of tumors from patients with advanced and metastatic cancers, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. Together, these studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and can modulate competitive fitness and MEK dependency.
2016-12-22 | GSE92682 | GEO
Project description:Oncogenic Ras mutations occur frequently in hematological malignancies. It was unclear if besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the development of the disease. We used microarray-based analysis of murine hematopoietic bone marrow (BM) cells harboring active inducible KrasG12D to reveal the expression of inflammation-related genes.
2020-02-29 | GSE131885 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
2023-06-09 | GSE234449 | GEO