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  3. Phosphoproteomic subtyping of gastric cancer reveals dynamic transformation with chemotherapy and guides targeted cancer treatment

Phosphoproteomic subtyping of gastric cancer reveals dynamic transformation with chemotherapy and guides targeted cancer treatment

  • Cell Rep. 2024 Oct 22;43(10):114774. doi: 10.1016/j.celrep.2024.114774.
Hirokazu Shoji 1,  Hidekazu Hirano 2,  Yosui Nojima 3,  Daigo Gunji 4,  Akina Shinkura 4,  Satoshi Muraoka 5,  Yuichi Abe 6,  Ryohei Narumi 7,  Chioko Nagao 8,  Masahiko Aoki 9,  Kazutaka Obama 10,  Kazufumi Honda 11,  Kenji Mizuguchi 8,  Takeshi Tomonaga 12,  Yutaka Saito 13,  Takaki Yoshikawa 14,  Ken Kato 15,  Narikazu Boku 16,  Jun Adachi 17
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo 104-0045, Japan. Electronic address: hshouji@ncc.go.jp.
  • 2 Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan; Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan.
  • 3 Center for Mathematical Modeling and Data Science, Osaka University, Osaka 560-8531, Japan; Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 566-0002, Japan.
  • 4 Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan; Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
  • 5 Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan; Laboratory of Clinical and Analytical Chemistry, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.
  • 6 Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan; Immunoproteomics Laboratory, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1112, Japan.
  • 7 Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan.
  • 8 Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 566-0002, Japan; Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
  • 9 Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  • 10 Department of Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
  • 11 Department of Bioregulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan.
  • 12 Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan; Proteobiologics Co., Ltd., Osaka 562-0011, Japan.
  • 13 Endoscopy Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  • 14 Department of Gastric Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  • 15 Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan; Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  • 16 Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan; Department of Medical Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. Electronic address: nboku@ims.u-tokyo.ac.jp.
  • 17 Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka 567-0085, Japan; Laboratory of Clinical and Analytical Chemistry, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Laboratory of Proteomics and Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. Electronic address: jun_adachi@nibiohn.go.jp.
PMID: 39357518 DOI: 10.1016/j.celrep.2024.114774
Abstract

There are only a few effective molecular targeted agents for advanced unresectable or recurrent advanced gastric Cancer (AGC), which has a poor prognosis with a median survival time of less than 14 months. Focusing on phosphorylation signaling in Cancer cells, we have been developing deep phosphoproteome analysis from minute endoscopic biopsy specimens frozen within 20 s of collection. Phosphoproteomic analysis of 127 fresh-frozen endoscopic biopsy samples from untreated patients with AGC revealed three subtypes reflecting different cellular signaling statuses. Subsequent serial biopsy analysis has revealed the dynamic mesenchymal transitions within Cancer cells, along with the concomitant rewiring of the kinome network, ultimately resulting in the conversion to the epithelial-mesenchymal transition (EMT) subtype throughout treatment. We present our investigation of intracellular signaling related to the EMT in gastric Cancer and propose therapeutic approaches targeting Axl. This study also provides a wealth of resources for the future development of treatments and biomarkers for AGC.

Keywords

AXL; CP: Cancer; EMT; endoscopic biopsy; gastric cancer; gilteritinib; phosphorylation signal; proteome; serial biopsy analysis.

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