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Oncogene-dependent regulation of tumor cells via stromal reciprocal signalling

ABSTRACT: Cancer is a heterocellular disease composed of tumor cells and stromal cells. Although stromal cells are known to regulate cancer progression, oncogene-dependent signalling through heterocellular cancer systems remains poorly elucidated. Here, we describe KRASG12D-dependent ‘reciprocal’ signalling across tumor and stromal Pancreatic Ductal Adenocarcinoma (PDA) cells. Heterocellular multivariate phosphoproteomics demonstrates how an oncogenic cue (KRASG12D), a trans-cellular signal (SHH), and stromal cells drive a reciprocal response in tumor cells. KRASG12D-dependent reciprocal signalling regulates the tumor cell phosphoproteome, total proteome, and mitochondria activity via an IGFR1/AXL-AKT axis. The reciprocal KRASG12D signalling state requires a heterocellular context and is unreachable by cell-autonomous oncogenic KRAS alone. These findings provide evidence that oncogenic KRAS regulates tumor cells via heterocellular reciprocation. Comparison between FACS resolved iKRAS cells (previously in co-culture with PSCs) pertubed with a SHH antibody

ORGANISM(S): Mus musculus

SUBMITTER: Hui Sun Leong

PROVIDER: E-GEOD-70351 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Oncogene-dependent regulation of tumor cells via stromal reciprocal signalling

Project description:Cancer is a heterocellular disease composed of tumor cells and stromal cells. Although stromal cells are known to regulate cancer progression, oncogene-dependent signalling through heterocellular cancer systems remains poorly elucidated. Here, we describe KRASG12D-dependent ‘reciprocal’ signalling across tumor and stromal Pancreatic Ductal Adenocarcinoma (PDA) cells. Heterocellular multivariate phosphoproteomics demonstrates how an oncogenic cue (KRASG12D), a trans-cellular signal (SHH), and stromal cells drive a reciprocal response in tumor cells. KRASG12D-dependent reciprocal signalling regulates the tumor cell phosphoproteome, total proteome, and mitochondria activity via an IGFR1/AXL-AKT axis. The reciprocal KRASG12D signalling state requires a heterocellular context and is unreachable by cell-autonomous oncogenic KRAS alone. These findings provide evidence that oncogenic KRAS regulates tumor cells via heterocellular reciprocation.

2015-06-27 | GSE70351 | GEO

ATAC-seq of pancreatic cancer cells derived from a genetically engineered mouse model, which harbor the inducible KrasG12D allele

Project description:Pancreatic adenocarcinoma (PDAC) is a lethal disease and it is the most common type of pancreatic cancer. Majority of the pancreatic cancers harbor alterations in the Kras gene. Currently there are no approved drugs that target Kras directly and it's downstream effect on the epigenome remains unknown. In this study, we investigated the epigenetic landscape of pancreatic cancer cells which harbor the inducible KrasG12D allele. We performed RNA-seq, ChIP-seq against 6 different histone marks, ATAC-seq and RRBS to assess the changes in the epigenome after oncogenic KrasG12D induction.

2021-09-19 | E-MTAB-10909 | biostudies-arrayexpress

ChIP-seq of pancreatic cancer cells derived from a genetically engineered mouse model, which harbor the inducible KrasG12D allele

2021-09-06 | E-MTAB-10901 | biostudies-arrayexpress

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.

2016-04-19 | PXD003223 | Pride

Mus musculus

Project description:Oncogene-dependent regulation of tumor cells via stromal reciprocal signalling

| PRJNA288372 | ENA

RNA-seq of pancreatic cancer cells derived from a genetically engineered mouse model, which harbor the inducible KrasG12D allele

2021-09-06 | E-MTAB-10896 | biostudies-arrayexpress

RNA-seq of pancreatic cancer cells (1012 and 9805) derived from a genetically engineered mouse model, which harbor the inducible KrasG12D allele

2021-09-14 | E-MTAB-10897 | biostudies-arrayexpress

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.

2021-01-07 | PXD018296 | Pride

RRBS of pancreatic cancer cells derived from a genetically engineered mouse model, which harbor the inducible KrasG12D allele

2021-09-06 | E-MTAB-10900 | biostudies-arrayexpress

Expression data from lung tumor and stromal cells of KrasTgfbr2 -/- mouse model

Project description:Recent data suggests that repression of the Type II TGF-B Receptor (Tgfr2) repression in human lung adenocarcinoma is important for progression from noninvasive to invasive adenocarcinoma. To test this hypothesis in a animal model of non-invasive lung cancer, we generated an inducible, lung specific Tgfbr2 knockout model in the oncogenic Kras mouse. LSL-KrasG12D positive mice were simultaneously backcrossed to C57/Bl6 mice and to the Tgfbr2 flox/flox mice. To induce tumors, 100 ul of saline containing 3x10e10 particles of an adenovirus containing the Cre recombinase (Ad.Cre) was administered to each LSL-KrasG12D mouse intra-nasally. We evaluated the tumor microenvironment response to Tgfbr2 deficient tumor cells. We compared lung tumor cell and stromal cell transcriptional profiles from five-week KrasTgfbr2 -/- and nine-week KrasTgfbr2 WT mice. We used mice at these time points to allow comparison of the stromal compartment of similarly advanced tumors.

2011-09-14 | E-GEOD-27675 | biostudies-arrayexpress

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