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Phenotype screens of genetically engineered mouse models of pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like perineural invasion

ABSTRACT: Phenotype screens of genetically engineered mouse models of pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like perineural invasion

PROVIDER: PRJNA833954 | ENA |

REPOSITORIES: ENA

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Phenotype screens of murine pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like neural invasion

Project description:Solid cancers like pancreatic cancer (PDAC) frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modelled in genetically-engineered mouse models (GEMM) of PDAC.Here, we systematically screened for human-like NI in Europe’s largest repository of GEMM of PDAC comprising 295 different genotypes. This phenotype screen uncovered two GEMM of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming-growth-factor-alpha (TGFa) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGFa upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI, and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGFa-expression constituted strong prognostic factors. Therefore, TGFa-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

2023-10-11 | GSE245126 | GEO

Phenotype screens of genetically engineered mouse models of pancreatic cancer identify a Tgfa-Ccl2-paxillin axis driving human-like perineural invasion

Project description:Solid cancers such as pancreatic cancer (PDAC) often exploit nerves for rapid spread. This neural invasion (NI) is an independent prognostic factor in PDAC and the main trigger for local recurrence and severe pain. However, genetically engineered mouse models (GEMM) of PDAC do not adequately represent the morphology of human NI. Therefore, we performed a systematic morphological screening of mutant mice with combinations of mutant alleles of oncogenes and tumour suppressors from our mouse repository. In a newly generated TPAC and TPC mouse mutant with pancreas-specific overexpression of transforming growth factor alpha (TGFa) and conditional deletion of p53, we identified human-like NI. To dissect the molecular mechanisms behind, we compared the transcriptome of TPAC and TPC mouse mutants with known KPC and KC mice lacking NI pathology. Our results revealed strong enrichment of genes encoding the extracellular matrix, including ECM glycoproteins, collagens and proteoglycans involved in biological oxidation, nuclear receptors, and proteins encoding drug metabolism via cytochrome P450 and retinoic acid signaling in TPAC cancer cells.

2022-05-05 | GSE201994 | GEO

Paxillin regulates genomic networks in prostate cancer [LNCaP]

Project description:We report that the adaptor protein, paxillin, regulates some androgen responsive genes in the castration sensitive prostate cancer cell line, LNCaP.

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Paxillin regulates genomic networks in prostate cancer [PC3]

Project description:We report that the adaptor protein, paxillin, regulates some proliferative and apoptotic genes in the castration resistant prostate cancer cell line, PC3.

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Paxillin regulates genomic networks in prostate cancer [C4-2]

Project description:We report that the adaptor protein, paxillin, regulates some androgen responsive genes in the castration resistant prostate cancer cell line,C4-2.

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Systematic Identification of Transcription Factors Driving Cell Fate Conversion using CRISPR Activation Screens

Project description:Systematic Identification of Transcription Factors Driving Cell Fate Conversion using CRISPR Activation Screens

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Paxillin regulates genomic networks in prostate cancer

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Mononuclear phagocytes in muscle after notexin injury in C57Bl/6, Cx3cr1-/-, Ccl2-/-,Cx3cr1-/-Ccl2-/- mice

Project description:Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2-/- mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is up-regulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2-/- mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.

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Noncanonical pathway for regulation of CCL2 expression by an mTORC1-FOXK1 axis promotes recruitment of tumor-associated macrophages

Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that is activated in various tumor cell types. We have now identified a noncanonical pathway for regulation of CCL2 production that is mediated by mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1, with dephosphorylation of FOXK1 in response to mTORC1 activation resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. Specific inhibition of FOXK1 may thus be a potential therapeutic strategy for cancer.

2017-11-30 | PXD007996 | Pride

NIS-lncRNA promotes neuropathic pain by increasing Ccl2 expression

Project description:Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.

2022-06-15 | GSE206043 | GEO

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