Identification of TPI1 As a potential therapeutic target in pancreatic cancer with dependency of TP53 mutation using multi-omics analysis

Tomoaki Toyoda; Nami Miura; Shingo Kato; Takeshi Masuda; Ryuji Ohashi; Akira Matsushita; Fumio Matsuda; Sumio Ohtsuki; Akira Katakura; Kazufumi Honda

doi:10.1111/cas.16302

Identification of TPI1 As a potential therapeutic target in pancreatic cancer with dependency of TP53 mutation using multi-omics analysis

Cancer Sci. 2024 Sep 11. doi: 10.1111/cas.16302. Online ahead of print.

Authors

Tomoaki Toyoda^{1

2}, Nami Miura³, Shingo Kato⁴, Takeshi Masuda^{5

6}, Ryuji Ohashi⁷, Akira Matsushita⁸, Fumio Matsuda⁹, Sumio Ohtsuki⁵, Akira Katakura², Kazufumi Honda^{1

3}

Affiliations

¹ Department of Bioregulation, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
² Department of Oral Pathobiological Science and Surgery, Tokyo Dental College, Tokyo, Japan.
³ Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
⁴ Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanazawa-ku, Japan.
⁵ Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
⁶ Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
⁷ Department of Integrated Diagnostic Pathology, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
⁸ Department of Gastroenterological Surgery, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
⁹ Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan.

PMID: 39259678
DOI: 10.1111/cas.16302

Abstract

Mutations of KRAS, CDKN2A, TP53, and SMAD4 are the four major driver genes for pancreatic ductal adenocarcinoma (PDAC), of which mutations of KRAS and TP53 are the most frequently recognized. However, molecular-targeted therapies for mutations of KRAS and TP53 have not yet been developed. To identify novel molecular targets, we newly established organoids with the Kras mutation (Kras^muOR) and Trp53 loss of function using Cre transduction and CRISPR/Cas9 (Kras^mu/p53^muOR) from murine epithelia of the pancreatic duct in Kras^LSL-G12D mice, and then analyzed the proteomic and metabolomic profiles in both organoids by mass spectrometry. Hyperfunction of the glycolysis pathway was recognized in Kras^mu/p53^muOR compared with Kras^muOR. Loss of function of triosephosphate isomerase (TPI1), which is involved in glycolysis, induced a reduction of cell proliferation in human PDAC cell lines with the TP53 mutation, but not in PDAC or in human fibroblasts without TP53 mutation. The TP53 mutation is clinically recognized in 70% of patients with PDAC. In the present study, protein expression of TPI1 and nuclear accumulation of p53 were recognized in the same patients with PDAC. TPI1 is a potential candidate therapeutic target for PDAC with the TP53 mutation.

Keywords: multi‐omics; organoid; p53; pancreatic cancer; triosephosphate isomerase 1 (TPI1).

Abstract

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