Wnt Pathway in Pancreatic Development and Pathophysiology

Abstract

The pancreas is an abdominal gland that serves 2 vital purposes: assist food processing by secreting digestive enzymes and regulate blood glucose levels by releasing endocrine hormones. During embryonic development, this gland originates from epithelial buds located on opposite sites of the foregut endoderm. Pancreatic cell specification and maturation are coordinated by a complex interplay of extrinsic and intrinsic signaling events. In the recent years, the canonical Wnt/β-catenin pathway has emerged as an important player of pancreas organogenesis, regulating pancreatic epithelium specification, compartmentalization and expansion. Importantly, it has been suggested to regulate proliferation, survival and function of adult pancreatic cells, including insulin-secreting β-cells. This review summarizes recent work on the role of Wnt/β-catenin signaling in pancreas biology from early development to adulthood, emphasizing on its relevance for the development of new therapies for pancreatic diseases.

Developmentally dynamic changes in DNA methylation in the human pancreas

“…Gene ontology (GO) analysis of genes annotated to the top 10,000 hypermethylated dDMPs identified a highly significant enrichment for multiple developmental pathways ( Supplementary Table 3 ). KEGG analysis revealed an enrichment of genes within the Wnt signaling pathway (FDR = 0.0011), a crucial pathway for cell fate determination and organogenesis that plays an important role in development of the pancreas (Murtaugh, 2008, Napolitano et al, 2023, Sharon et al, 2019), and insulin secretion (FDR = 0.088) (Supplementary Table 4) . GO analysis of genes annotated to the top 10,000 hypomethylated dDMPs revealed an enrichment of genes involved in catalytic activity (FDR = 6.87 × 10 −8 ) and other catabolic processes (FDR = 3.12 × 10 −7 ) ( Supplementary Table 5 ).…”

Solid tumor growth depends on an intricate equilibrium of malignant cell states

“…In the context of PDAC, this growth control is directed by coordinated WNT and Notch signals that instruct malignant cell differentiation, which, in turn, gates KRAS-driven proliferation in PDAC. Specification of pancreatic progenitors from the foregut requires inhibition of WNT signaling, whereas expansion of that tissue is promoted by WNT signaling 37 . In later stages of development, WNT promotes differentiation of pancreatic progenitors into acinar cells 37 .…”

“…Specification of pancreatic progenitors from the foregut requires inhibition of WNT signaling, whereas expansion of that tissue is promoted by WNT signaling 37 . In later stages of development, WNT promotes differentiation of pancreatic progenitors into acinar cells 37 . Furthermore, WNT signaling contributes to injury responses in the pancreas: WNT ligands and nuclear β-catenin are required for reacquisition of the acinar fate following acinar-to-ductal metaplasia (ADM) – an essential process in pancreas injury repair 38 .…”

Diabetic peripheral neuropathy: pathogenetic mechanisms and treatment

“…This Wnt ligand can bind to the receptors of the frizzled protein family to activate various downstream signaling pathways ( 123 ). The Wnt protein located outside the cell can activate three intracellular transduction cascades: the canonical Wnt/β-catenin pathway, the non-canonical planar cell polarity pathway, and the Wnt/Ca 2+ pathway ( 124 ).…”