Xiaohua Duan, Tuo Zhang, Lingling Feng, Neranjan de Silva, Benjamin Greenspun, Xing Wang, Jenna Moyer, M. Laura Martin, Rohit Chandwani, Olivier Elemento, Steven D. Leach, Todd Evans, Shuibing Chen, Fong Cheng Pan
{"title":"A pancreatic cancer organoid platform identifies an inhibitor specific to mutant KRAS","authors":"Xiaohua Duan, Tuo Zhang, Lingling Feng, Neranjan de Silva, Benjamin Greenspun, Xing Wang, Jenna Moyer, M. Laura Martin, Rohit Chandwani, Olivier Elemento, Steven D. Leach, Todd Evans, Shuibing Chen, Fong Cheng Pan","doi":"10.1016/j.stem.2023.11.011","DOIUrl":null,"url":null,"abstract":"<p><span>KRAS<span> mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRAS</span></span><sup>G12C</sup> suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the Kras<sup>G12D</sup> mutation both <em>in vitro</em> and <em>in vivo</em><span><span> and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator </span>SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.</span></p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"43 1","pages":""},"PeriodicalIF":19.8000,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.stem.2023.11.011","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0
Abstract
KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the KrasG12D mutation both in vitro and in vivo and primary human PDAC organoids. scRNA-seq analysis suggests that the cholesterol synthesis pathway is upregulated specifically in the KRAS mutant organoids, including the key cholesterol synthesis regulator SREBP2. Perhexiline maleate decreases SREBP2 expression levels and reverses the KRAS mutant-induced upregulation of the cholesterol synthesis pathway.
期刊介绍:
Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.