Trinh, V. Q.-H. | bioRxiv Science

bioRxiv2024

Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas

BACKGROUND & AIMSIntraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recent studies have shown that pancreatic precancer is characterized by a transcriptomic program similar to gastric metaplasia. The aims of this study were to assay IPMN for pyloric markers, to identify molecular drivers, and to determine a functional role for this program in the pancreas. METHODSPyloric marker expression was evaluated by RNA-seq and multiplex immunostaining in patient samples. Cell lines and organoids expressing KrasG12D +/- GNASR201C underwent RNA sequencing. A PyScenic-based regulon analysis was performed to identify molecular drivers, and candidates were evaluated by RNA-seq, immunostaining, and small interfering RNA knockdown. Glycosylation profiling was performed to identify GNASR201C-driven changes. Glycan abundance was evaluated in patient samples. RESULTSPyloric markers were identified in human IPMN. GNASR201Cdrove expression of this program as well as an indolent phenotype characterized by distinct glycosyltransferase changes. Glycan profiling identified an increase in LacdiNAcs and loss of pro-tumorigenic Lewis antigens. Knockdown of transcription factors Spdef or Creb3l1 or chitinase treatment reduced LacdiNAc deposition and reversed the indolent phenotype. LacdiNAc and 3-sulfoLeA/C abundance discriminated low from high grade patient IPMN. CONCLUSIONGNASR201C drives an indolent phenotype in IPMN by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1 which is characterized by distinct glycans. Acting as a glycan rheostat, mutant GNAS elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAc and 3-Sulfo-LeA/C are mutually exclusive and may serve as markers of disease progression.

cancer biology↗

bioRxiv2023

Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling

Organ homeostasis is maintained by regulated proliferation of distinct cell populations. In mouse liver, cyclin D1-positive hepatocytes in the midlobular zone repopulate the parenchyma at a constant rate to preserve liver homeostasis. The mitogenic cues that underlie this process are unknown. Hepatic stellate cells, the livers pericytes, are in close proximity to hepatocytes and have been implicated in supporting hepatocyte proliferation, but their role in liver homeostasis is unknown. Here, we employ a T cell-mediated hepatic stellate cell ablation model to remove nearly all hepatic stellate cells in the murine liver, enabling the unbiased characterization of hepatic stellate cell functions. In the normal murine liver, complete loss of hepatic stellate cells persists for up to 6 weeks and reduces liver mass. Our results show that hepatic stellate cells induce cyclin D1 in midlobular hepatocytes by release of neurotrophin-3 to promote hepatocyte proliferation via tropomyosin receptor kinase B signaling. These findings establish that hepatic stellate cells form the niche for midlobular hepatocytes and reveal a novel hepatocyte growth factor signaling pathway. One-Sentence SummaryHepatic stellate cells provide mitogenic cues for midlobular hepatocyte proliferation and metabolic zonation by secreting neurotrophin-3.

cell biology↗