2. Academic Validation
  3. Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis

Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis

  • Gastroenterology. 2024 Jan 24:S0016-5085(24)00064-7. doi: 10.1053/j.gastro.2024.01.027.
Yoonkyung Won 1,  Bogun Jang 2,  Su-Hyung Lee 1,  Michelle L Reyzer 3,  Kimberly S Presentation 1,  Hyesung Kim 4,  Brianna Caldwell 1,  Changqing Zhang 1,  Hye Seung Lee 5,  Cheol Lee 6,  Vincent Q Trinh 7,  Marcus C B Tan 8,  Kwangho Kim 9,  Richard M Caprioli 3,  Eunyoung Choi 10
Affiliations

Affiliations

  • 1 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • 2 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Jeju National University College of Medicine and Jeju National University Hospital, Jeju, Republic of Korea.
  • 3 Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee.
  • 4 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Jeju National University College of Medicine, Jeju, Republic of Korea.
  • 5 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 6 Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 7 The Digital Histology and Advanced Pathology Research, The Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal, Montréal, Québec, Canada.
  • 8 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • 9 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee.
  • 10 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee. Electronic address: [email protected].
PMID: 38272100 DOI: 10.1053/j.gastro.2024.01.027
Abstract

Background & aims: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous 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, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells.

Methods: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic 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- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers.

Results: 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 up-regulated during carcinogenesis in human gastrointestinal cancers.

Conclusions: 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.

Keywords

Carcinogenesis; Fatty Acid Metabolism; Imaging Mass Spectrometry; Kras; Stearoyl-CoA Desaturase.

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