Mouse models of Kras activation in gastric cancer

www.nature.com/emm REVIEW ARTICLE OPEN Mouse models of Kras activation in gastric cancer Yoonkyung Won1,2 and Eunyoung Choi 1,2,3 ✉ © The Author(s) 2022 1234567890();,: Gastric cancer has one of the highest incidence rates and is one of the leading causes of cancer-related mortality worldwide. Sequential steps within the carcinogenic process are observed in gastric cancer as well as in pancreatic cancer and colorectal cancer. Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most well-known oncogene and can be constitutively activated by somatic mutations in the gene locus. For over 2 decades, the functions of Kras activation in gastrointestinal (GI) cancers have been studied to elucidate its oncogenic roles during the carcinogenic process. Different approaches have been utilized to generate distinct in vivo models of GI cancer, and a number of mouse models have been established using Kras-inducible systems. In this review, we summarize the genetically engineered mouse models in which Kras is activated with cell-type and/or tissue-type specificity that are utilized for studying carcinogenic processes in gastric cancer as well as pancreatic cancer and colorectal cancer. We also provide a brief description of histological phenotypes and characteristics of those mouse models and the current limitations in the gastric cancer field to be investigated further. Experimental & Molecular Medicine (2022) 54:1793–1798; https://doi.org/10.1038/s12276-022-00882-1 INTRODUCTION The gastrointestinal (GI) tract, as a part of the digestive system, includes the esophagus, stomach, pancreas, small intestine and colon; the GI tract is where foods and liquids enter into the body and are digested and nutrients are absorbed1. GI cancers represent a substantial proportion of cancer incidence and mortality worldwide2. GI cancers develop in a sequential carcinogenic process through a series of preneoplastic lesions. In the stomach, intestinal-type gastric cancer is the most common cancer type and is associated with environmental factors, such as acute mucosal injury by toxic drugs and chronic inflammation caused by Helicobacter pylori infection3,4. Intestinal-type gastric cancer develops within these preneoplastic metaplastic lesions from normal mucosal changes through chronic gastritis with mucosal atrophy and a multistep process, which involves the progression of preneoplastic pyloric metaplasia and intestinal metaplasia (IM) to neoplastic dysplasia and adenocarcinoma. These sequential changes were first described as the Correa pathway by Pelayo Correa5. Pyloric metaplasia can initially arise following acid-secreting parietal cell atrophy through the transdifferentiation of zymogen granule-secreting chief cells into metaplastic cells, called spasmolytic polypeptide-expressing metaplasia (SPEM) cells, in response to mucosal injury6–9. While this initial process is potentially reversible, cell plasticity also permits the entry of metaplastic cells into carcinogenic transition, leading to the progression of reversible pyloric metaplasia to irreversible IM and neoplastic dysplasia10,11. This carcinogenic cascade is also observed in other GI tract cancers, such as esophageal, pancreatic and colorectal cancers12–14. In pancreatic carcinogenesis, several types of preneoplastic lesions have been identified, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN) and mucinous cystic neoplasia (MCN)15. PanINs are characterized by a stepwise acquisition of mutations in Kras and Trp53 genes from low-grade dysplasia (PanIN 1-2) to carcinoma in situ (PanIN 3)16. Colorectal cancer also develops from the progression of acquired or hereditary premalignant lesions17,18. Colorectal carcinogenesis progresses from hyperproliferative regions in the normal colonic mucosa designated as polyps into early and late adenoma and finally carcinoma14,19. Mutations influencing members of the rat sarcoma viral oncogene family (RAS) genes (KRAS, NRAS, HRAS) are the most frequent genetic alterations in human cancers, accounting for approximately 30% of all tumors20. Ras proteins function as a simple binary ON–OFF molecular switch through the function of guanosine triphosphatase (GTPase), which controls cycles between an active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound state21. Kras is predominantly inactive and GDP-bound in quiescent cells, while it is active and GTP-bound in active cells where extracellular stimuli activate receptor tyrosine kinases (RTKs) and other cell surface receptors. In cancers, the Ras genes harbor missense mutations that encode single amino acid substitutions primarily at one of three mutational spots: glycine-12 (G12), glycine-13 (G13), or glutamine-61 (Q61). These mutations block GTPase-activating proteins (GAPs) from accessing GTP, and hydrolysis is prevented, resulting in persistent activation of the GTP-bound state22. In 1982, the Kras gene was the first oncogene identified in human cancer23 and one of the proto-oncogenes predominantly mutated in many GI cancers, including pancreatic, gastric, and colorectal cancer24–27. Because of various incidence rates and roles of Kras activation in different GI cancers, numerous studies have been performed to elucidate the oncogenic mechanisms of Kras in GI carcinogenesis11,28–36. 1 Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. 2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. 3Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA. ✉email: Received: 31 July 2022 Revised: 6 September 2022 Accepted: 8 September 2022 Published online: 11 November 2022 Y. Won and E. Choi 1794 Table 1. Genetically engineered mouse models of pancreatic cancer. GEMM References Pdx1-Cre; LSL-KrasG12D/+ Hingorani et al., 2003 Ptf1a(P48)-Cre; LSL-KrasG12D/+ Ela-CreERT2; LSL-KrasG12D/+ Habbe et al., 2008 Mist1-CreERT2; LSL-KrasG12D/+ Pdx1-CreERT; LSL-KrasG12D/+ Pdx1-CreERT; LSL-KrasG12D/+;Trp53fl/fl Gidekel Friedlander et al., 2009 Pdx1-CreERT; LSL-KrasG12D/+;Ink4a/Arffl/ fl ProCPA1-CreERT2; LSL-KrasG12D/+ ProCPA1-CreERT2; LSL-KrasG12D/ + ;Trp53fl/fl of all gastric cancer cases, signatures for the activation and amplification of Kras are noted in at least 40% of human intestinaltype gastric cancers. On the other hand, KRAS mutations are observed in approximately 90% of pancreatic cancer patients, and mutations in tumor suppressors such as CDKN2A/p16INK4A, Trp53, and SMAD4 are also common in pancreatic cancer. Of note, Kras mutations are an early oncogenic event in pancreatic carcinogenesis49–53. Colorectal cancer also develops through a series of germline or somatic mutations, which affect the homeostasis of oncogenes or tumor suppressors. A large proportion of somatic mutations have been identified in colorectal cancer, including mutations in Trp53, APC, KRAS, P (...truncated)