Toward a CRISPR- based mouse model of Vhl- deficient clear cell kidney cancer: Initial experience and lessons learned

• 成果类型: Article
• 署名作者: Stransky, Laura A.; Gao, Wenhua; Schmidt, Laura S.; Bi, Kevin; Ricketts, Christopher J.; Ramesh, Vijyendra; James, Amy; Difilippantonio, Simone; Ileva, Lilia; Kalen, Joseph D.; Karim, Baktiar; Jeon, Albert; Morgan, Tamara; Warner, Andrew C.; Turan, Sevilay; Unite, Joanne; Tran, Bao; Choudhari, Sulbha; Zhao, Yongmei; Linn, Douglas E.; Yun, Changhong; Dhandapani, Sripriya; Parab, Vaishali; Pinheiro, Elaine M.; Morris, Nicole; He, Lixia; Vigeant, Sean M.; Pignon, Jean- Christophe; Ivins, Maura Sticco --; Signoretti, Sabina; Allen, Eliezer M. Van; Linehan, W. Marston; Kaelin, William G.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Merck & Company; Merck & Company USA; Merck & Company; Merck & Company USA; Merck & Company; Merck & Company USA; Merck & Company; Merck & Company USA; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12549
• DOI: 10.1073/pnas.2408549121
• 发表日期: 2024-10-08
• 关键词: hypoxia-inducible factor; carcinoma; Mutation; inactivation; expression; mice; hif; inhibition; suppression; hif2-alpha

摘要

CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus- associated viruses (AAVs) encoding sgRNAs against VHL and other known/ suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney- specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1, and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard- of- care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent.