Biology subjects

Sontz, R. A.

Publications and source records attributed to Sontz, R. A..

2 recordsLinked to original sources

bioRxiv2022

GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

BACKGROUND & AIMSEfforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive model systems that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a role for enteric glia in neuroendocrine cell specification. Here we investigated the hypothesis that loss of menin in glial cells stimulated neuroendocrine differentiation and tumorigenesis. METHODSUsing Cre-lox technology, we generated a conditional glial fibrillary acidic protein-directed Men1 knockout (GFAP{Delta}Men1) mouse model. Cre specificity was confirmed using a tdTomato reporter. GFAP{Delta}Men1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. siRNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel. RESULTSGFAP{Delta}Men1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAP{Delta}Men1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Mechanistically, Men1 deletion induced reprogramming from a mature glial phenotype toward a neuroendocrine lineage. Furthermore, blockade of Hedgehog signaling in enteric glia attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. CONCLUSIONSGFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/479845v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1118702org.highwire.dtl.DTLVardef@1b6cc3forg.highwire.dtl.DTLVardef@1b4949org.highwire.dtl.DTLVardef@168704b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Toll Like Receptor 9 Pathway Mediates Schlafen+-MDSC Polarization During Helicobacter-Induced Gastric Metaplasias

Background and AimsA subset of MDSCs that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter-inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that individuals with a more robust response to damage-activated molecular patterns (DAMPs) and increased Toll-like receptor (TLR9) expression are predisposed to the neoplastic complications of Helicobacter infection. MethodsA mouse or human Transwell co-culture system comprised of dendritic cells (DCs), 2-dimensional gastric epithelial monolayers and Helicobacter were used to dissect the cellular source of interferon (IFN) in the stomach by flow cytometry. Conditioned media from the cocultures polarized primary myeloid cells. Myeloid-derived suppressor cell (MDSC) activity was determined by T cell suppression assays. In human subjects with intestinal metaplasia or gastric cancer, the rs5743836 TLR9T>C variant was genotyped and linked to TLR9, IFN and SLFN12L expression by immunohistochemistry. NF{kappa}B binding to the TLR9 C allele was determined by electrophoretic mobility shift assays. ResultsHelicobacter infection induced gastric epithelial and plasmacytoid DC expression of TLR9 and IFN. Co-culturing primary mouse or human cells with DCs and Helicobacter induced TLR9, IFN secretion and SLFN+-MDSC polarization. Neutralizing IFN in vivo mitigated Helicobacter-induced SPEM. The TLR9 minor C allele creates an NF{kappa}b binding site associated with higher levels of TLR9, IFN and SLFN12L in Helicobacter-infected stomachs that correlated with a greater incidence of metaplasias and cancer. ConclusionTLR9 plays an essential role in the production of IFN and polarization of SLFN+-MDSCs upon Helicobacter infection. Subjects carrying the rs5743836 TLR9 minor C allele are predisposed to neoplastic complications if chronically infected.

cancer biology↗