{"doi":"10.1016/j.jcmgh.2022.06.004","title":"Stroma New Tune: Emerging Role of PKA in Maintaining Gastric Homeostasis","abstract":"The stomach is a complex organ, comprising 2 distinct anatomic compartments (the corpus and antrum) and a diverse array of epithelial cell types that interact by an intricate but poorly understood communications network. In the corpus, isthmal stem cells replenish lost cells in the superficial pit region and cells deeper in the gland (mucous neck and parietal cells) that coordinate acid production. Gastric glands also harbor neuroendocrine cells that secrete hormones, such as ghrelin. At the base of gastric glands reside digestive-enzyme-secreting chief cells that can also serve as reserve stem cells after injury through an evolutionarily conserved program known as paligenosis.1Willet S.G. Lewis M.A. Miao Z.F. Liu D. Radyk M.D. Cunningham R.L. Burclaff J. Sibbel G. Lo H.G. Blanc V. Davidson N.O. Wang Z.N. Mills J.C. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis.EMBO J. 2018; 37e98311Crossref PubMed Scopus (76) Google Scholar Despite emerging understanding of the roles of those epithelial cell types, little is known about the functional and structural significance of the mesenchymal components (eg, fibroblasts, myofibroblasts, endothelial cells) that provide structure and support for the glands. It has been shown that the bone morphogenic protein (BMP) and extracellular signal-related kinase (ERK) pathways help maintain homeostasis in the stomach by influencing the mesenchymal-epithelial interaction, and aberrant signaling in these pathways can potentially lead to tumorigenesis. But it is unclear how these pathways are regulated intrinsically and extrinsically.2Shinohara M. Mao M. Keeley T.M. El-Zaatari M. Lee H.-J. Eaton K.A. Samuelson L.C. Merchant J.L. Goldenring J.R. Todisco A. Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.Gastroenterology. 2010; 139: 2050-2060Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,3Kikuchi Y. Kunita A. Iwata C. Komura D. Nishiyama T. Shimazu K. Takeshita K. Shibahara J. Kii I. Morishita Y. Yashiro M. Hirakawa K. Miyazono K. Kudo A. Fukayama M. Kashima T.G. The niche component periostin is produced by cancer-associated fibroblasts, supporting growth of gastric cancer through ERK activation.Am J Pathol. 2014; 184: 859-870Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Puri et al4Pawan Puri G.G. Faraj R. Gibson L. Gilbreath E. Yoder B.K. Elevated PKA activity in stomach mesenchyme disrupts mesenchymal-epithelial crosstalk and induces preneoplasia.Cell Mol Gastroenterol Hepatol. 2022; (XX:XXX–XXX)Google Scholar have now addressed the stromal knowledge gap by unveiling another player in the understudied gastric mesenchymal compartment: protein kinase A (PKA). Using a mesenchymal cell–specific Cre recombinase (Six2-Cre), and a PKA catalytic subunit mutant (PKAcαR) that lacks the ability to bind to its regulatory subunit, and hence enables a constitutively active form of PKA, the authors showed that aberrant expression of PKA leads to disruption of key signaling pathways, ultimately resulting in a state of disrupted gastric epithelial homeostasis that may enable tumorigenesis. The most obvious phenotype of these mice with altered PKA was noted in the epithelial cell compartment of the stomach corpus: a reduction in the number of key mature cell types that constitute the stomach corpus (parietal, chief, pit cells, and, to a lesser degree, neuroendocrine cells). The changes in cell census were associated with an increase (hyperplasia) in mucous neck cells and induction of spasmolytic polypeptide-expressing metaplasia. The glandular metaplasia pattern was accompanied by distinct morphologic alteration (most notably with severe cystic dilatations), chronic inflammatory changes, and aberrant STAT3 activation that has been previously identified as one of the key drivers in tumorigenesis.5Corcoran R.B. Contino G. Deshpande V. Tzatsos A. Conrad C. Benes C.H. Levy D.E. Settlema","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2022,"id":309625,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":91912,"name":"Jason C. Mills","orcid":"0000-0002-0402-4662","position":1,"is_corresponding":false},{"id":296996,"name":"Charles J. Cho","orcid":null,"position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T00:33:11.579763Z","pmid":"35793768","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}