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KrasG12D/+ co-mutation alters the transcriptional landscape of lung adenocarcinoma

ABSTRACT: KrasG12D/+ co-mutation alters the transcriptional landscape of lung adenocarcinoma

PROVIDER: PRJNA798368 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17653707_1.fastq.gz	Fastqsanger.gz
	SRR17653707_2.fastq.gz	Fastqsanger.gz
	SRR17653708_1.fastq.gz	Fastqsanger.gz
	SRR17653708_2.fastq.gz	Fastqsanger.gz
	SRR17653709_1.fastq.gz	Fastqsanger.gz

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KrasG12D/+ co-mutation alters the transcriptional landscape of lung adenocarcinoma

Project description:The tumor microenvironment (TME) contains a rich source of nutrients that sustain cell growth and ultimately facilitate tumor progression. The availability of glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert anti-tumor function. Recently, inhibition of glutaminase, the enzyme that hydrolyzes glutamine to glutamate, has garnered interest as an approach to both decrease tumor metabolism and growth, while increasing available glutamine in the TME for effector T cells. Checkpoint blockade immunotherapy unleashes anti-tumor effector capabilities of T cells, and although there are good responses in many solid tumors, a significant proportion of patients respond poorly. In lung adenocarcinoma, response to immunotherapy is reported to be impaired in KRAS-mutant patients harboring concurrent KEAP1 and STK11/Lkb1 mutations. To investigate the metabolism and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated a series of murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape seen in patients. Here we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1 checkpoint immunotherapy. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and cytotoxic activation of tumor-infiltrating CD8 T cells. Thus, CD8 T cells exposed to checkpoint immunotherapy have a dependence on glutamine and reliance on glutaminase activity and are negatively impacted by the glutaminase inhibitor in this highly activated state. Therefore, we discern that the combination of immunotherapy and glutaminase inhibition is not efficacious for CD8 T cell activation in the tumor microenvironment.

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Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma

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.

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Mouse models for pancreatic ductal adenocarcinoma areaffected by the cre-driver used to promote KRASG12D activation

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.

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Transcriptional profiling of intestinal changes following KRasG12D mutation in an APC deficient mutation

Project description:Transcriptional profiling of intestinal changes following KRasG12D mutation in an APC deficient mutation

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Single cell RNA sequencing of tumor sections from GEMM harboring KrasG12D/+ or KrasG12D/+Lkb1fl/fl(KL) mutation.

Project description:Single cell RNA sequencing of tumor sections from GEMM harboring KrasG12D/+ or KrasG12D/+Lkb1fl/fl(KL) mutation.

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mTORC1 and mTORC2 converge on the Arp2/3 complex to promote KrasG12D-induced acinar-to-ductal metaplasia and early pancreatic carcinogenesis

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.

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Next Generation Sequencing Quantitative Analysis of altered expression of genes in KRASG12D PDAC tissues

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Understanding transcriptional profile of alveolar Type I, Type II and double positive (Type I/II+) cells upon KrasG12D activation in mouse lungs during lung adenocarcinoma.

Project description:Previously, we identifed alveolar Type II cells as cell-of-origin for Kras induced lung adenocarcinoma. In the current study, we examined the phenotype of Type II cells after Kras activation and found evidence for proliferation of cells that co-express Type I and Type II markers. Using RNAseq, we are trying to charcterize these different alveolar epithelial cells (Type I, Type II and double positive (Type I/II+)) upon KrasG12D activation during lung adenocarcinoma.

2023-05-09 | GSE230664 | GEO

Pten deficiency cooperates with KrasG12D to activate NFkB pathway promoting the development of malignant pancreatic ductal adenocarcinoma

Project description:Almost all human pancreatic ductal adenocarcinomas (PDACs) are driven by oncogenic Kras and the progression of the disease is characterized by the serial appearance of certain genetic lesions. Mouse models have convincingly shown that Kras mutation induces classical PanIN lesions that can progress to PDAC in the appropriate tumor suppressor background. However, the cooperative mechanism between mutant Kras-dependent signaling surrogates and other oncogenic pathways remains to be fully elucidated in order to devise better therapeutic strategy. Mounting evidence PTEN/PI3K perturbation on PDAC tumorigenesis, we observed frequent PTEN inactivation at both genomic and histopathological levels in primary human PDAC samples. The importance of PTEN/PI3K pathway during the development of PDAC was further supported by genetic studies demonstrating that Pten deficiency in cooperation with Kras activation accelerated the formation of invasive PDAC. Mechanistically, combined Kras mutation and Pten inactivation leads to NFkB activation and subsequent induction of cytokine pathways, accompanied with strong stromal activation and immune cell infiltration. Therefore, PTEN/PI3K pathway dictates the activity of NFkB network and serves as a major surrogate during Kras-mediated pancreatic tumorigenesis. Primary pancreatic ductal epithelial cell cultures were established from 6 week old Pdx1-Cre;LSL-KrasG12D L/+ (n=3) or Pdx1-Cre;LSL-KrasG12D L/+;Pten L/+ (n=5) mice. Total RNA was collected from early passage cells.

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Project description:Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma

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