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Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE109289 | GEO | 2018/12/20

REPOSITORIES: GEO

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Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives serrated intestinal cancer

Project description:The serrated adenocarcinoma subtype accounts for 15-30% of all colorectal cancers (CRCs) and is aggressive and treatment-resistant. it is an alternative mechanism for CRC development characterized by dysregulation of the MAPK pathway. We show that human serrated tumors display reduced expression of PKCz and PKCl/i, and that the simultaneous inactivation of these genes in the mouse intestinal epithelium resulted in spontaneous tumorigenesis through the serrated pathway that progressed to advanced cancer. Whereas epithelial PKCl/i deficiency led to immunogenic cell death that repressed tumor initiation, interferon and CD8+ T cell responses were impaired concomitant with stromal activation and immunosuppression driven by PKCz loss. Thus, PKCz and PKCl/i cooperatively suppress serrated tumorigenesis. Targeting this stromal activation and immunosuppression showed synergistic curative activity.

2018-12-20 | GSE109288 | GEO

Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway [IECs DKO aPKC]

2018-12-20 | GSE109286 | GEO

Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance.

Project description:Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ? (PKC?) and PKC?/? was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKC?/? deficiency led to immunogenic cell death and the infiltration of CD8+ T cells, which repressed tumor initiation, PKC? loss impaired interferon and CD8+ T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-? receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC.

| S-EPMC6301096 | biostudies-literature

Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives serrated intestinal cancer

Project description:Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives serrated intestinal cancer

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Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway

Project description:Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway

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Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway [IECs DKO aPKC]

Project description:Impaired immunosurveillance by the simultaneous loss of both atypical PKCs drives intestinal cancer through the serrated pathway [IECs DKO aPKC]

| PRJNA430359 | ENA

Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation.

Project description:Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.

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Identification of Key Phospholipids That Bind and Activate Atypical PKCs.

Project description:PKCζ and PKCι/λ form the atypical protein kinase C subgroup, characterised by a lack of regulation by calcium and the neutral lipid diacylglycerol. To better understand the regulation of these kinases, we systematically explored their interactions with various purified phospholipids using the lipid overlay assays, followed by kinase activity assays to evaluate the lipid effects on their enzymatic activity. We observed that both PKCζ and PKCι interact with phosphatidic acid and phosphatidylserine. Conversely, PKCι is unique in binding also to phosphatidylinositol-monophosphates (e.g., phosphatidylinositol 3-phosphate, 4-phosphate, and 5-phosphate). Moreover, we observed that phosphatidylinositol 4-phosphate specifically activates PKCι, while both isoforms are responsive to phosphatidic acid and phosphatidylserine. Overall, our results suggest that atypical Protein kinase C (PKC) localisation and activity are regulated by membrane lipids distinct from those involved in conventional PKCs and unveil a specific regulation of PKCι by phosphatidylinositol-monophosphates.

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Malaria exposure drives both cognate and bystander human B cells to adopt an atypical phenotype.

Project description:Atypical memory B cells (aMBCs) are found in elevated numbers in individuals exposed to malaria. A key question is whether malaria induces aMBCs as a result of exposure to Ag, or non-Ag-specific mechanisms. We identified Plasmodium and bystander tetanus toxoid (TT) specific B cells in individuals from areas of previous and persistent exposure to malaria using tetramers. Malaria-specific B cells were more likely to be aMBCs than TT-specific B cells. However, TT-specific B cells from individuals with continuous exposure to malaria were more likely to be aMBCs than TT-specific B cells in individuals from areas where transmission has ceased. Finally, sequences of BCRs specific for a blood stage malaria-Ag were more highly mutated than sequences from TT-specific BCRs and under strong negative selection, indicative of ongoing antigenic pressure. Our data suggest both persistent Ag exposure and the inflammatory environment shape the B-cell response to malaria and bystander Ags.

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Atypical PKCs in memory maintenance: the roles of feedback and redundancy.

Project description:Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMζ and PKCι/λ, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated.

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