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

Hirokazu Shoji¹, Hidekazu Hirano², Yosui Nojima³, Daigo Gunji⁴, Akina Shinkura⁴, Satoshi Muraoka⁵, Yuichi Abe⁶, Ryohei Narumi⁷, Chioko Nagao⁸, Masahiko Aoki⁹, Kazutaka Obama¹⁰, Kazufumi Honda¹¹, Kenji Mizuguchi⁸, Takeshi Tomonaga¹², Yutaka Saito¹³, Takaki Yoshikawa¹⁴, Ken Kato¹⁵, Narikazu Boku¹⁶, Jun Adachi¹⁷

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

Free article

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

Hirokazu Shoji et al. Cell Rep. 2024.

Free article

. 2024 Oct 22;43(10):114774.

doi: 10.1016/j.celrep.2024.114774. Epub 2024 Oct 1.

Authors

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests T.T. and J.A. are co-founders of Proteobiologics Co., Ltd.

References

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous