YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration

Cell Rep. 2023 Dec 26;42(12):113497. doi: 10.1016/j.celrep.2023.113497. Epub 2023 Nov 30.

Abstract

Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.

Keywords: CP: Stem cell research; HIPPO pathway; YAP signaling; gastric cancer; metaplasia; peptic ulcer; regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gastric Mucosa / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Metaplasia / metabolism
  • Peptides* / metabolism
  • Stomach
  • Stomach Neoplasms* / genetics

Substances

  • spasmolytic polypeptide
  • Peptides
  • Intercellular Signaling Peptides and Proteins