YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration
Adrian K.H. Loe,
Abilasha Rao-Bhatia,
Zhao Wei,
Jung-Eun Kim,
Bingxin Guan,
Yan Qin,
Minji Hong,
Hyo Sang Kwak,
Xiaoyu Liu,
Leyi Zhang,
Jeffrey L. Wrana,
Haiyang Guo,
Tae-Hee Kim
Affiliations
Adrian K.H. Loe
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Abilasha Rao-Bhatia
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Zhao Wei
Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China
Jung-Eun Kim
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Bingxin Guan
Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China
Yan Qin
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Minji Hong
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Hyo Sang Kwak
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Xiaoyu Liu
Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China
Leyi Zhang
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Jeffrey L. Wrana
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
Haiyang Guo
Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China; Corresponding author
Tae-Hee Kim
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author
Summary: 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.
