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Vanderbilt University Medical Center

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Gastroenterology, Jan 23 2024, S0016-5085(24)00064-7 | https://doi.org/10.1053/j.gastro.2024.01.027 Oncogenic fatty acid metabolism rewires energy supply chain in gastric carcinogenesis

Yoonkyung Won^1,2, Bogun Jang ^1,2,3, Su-Hyung Lee ^1,2, Michelle L. Reyzer⁴, Kimberly S. Presentation ^1,2, Hyesung Kim ^1,2,5, Brianna Caldwell^1,2, Changqing Zhang ^1,2, Hye Seung Lee ^6,7, Cheol Lee ⁷, Vincent Q. Trinh ⁸, Marcus C.B. Tan ^1,2,9, Kwangho Kim ^10,11, Richard M. Caprioli ⁴, Eunyoung Choi ^1,2,12

¹Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

²Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA

³Department of Pathology, Jeju National University College of Medicine and Jeju National University Hospital, Jeju, Republic of Korea

⁴Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN, USA

⁵Jeju National University College of Medicine, Jeju, Republic of Korea

⁶Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

⁷Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea

⁸The Digital Histology and Advanced Pathology Research, The Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal, Montréal, Québec, Canada

⁹Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

¹⁰Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA

¹¹Department of Chemistry, Vanderbilt University, Nashville, TN, USA

¹²Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA

Correspondence: Eunyoung Choi, PhD

Abstract

Gastric carcinogenesis develops within a sequential carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, it remains unclear how metabolic changes contribute to the progression of metaplasia to dysplasia. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. We generated a Gif-rtTA;TetO-Cre;Kras ^G12D (GCK) mouse model which continuously induces active Kras expression in chief cells following doxycycline treatment. Histological examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl-CoA desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel Eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was upregulated during carcinogenesis in human gastrointestinal cancers. Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high energy demand in dysplastic cells.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-29)
연구진국내+국외 연구진
분야 의약학 > 종양의학

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