Toward a CRISPR-based mouse model of Vhl -deficient clear cell kidney cancer: Initial experience and lessons learned,Proceedings of the National Academy of Sciences of the United States of America

当前位置： X-MOL 学术 › Proc. Natl. Acad. Sci. U.S.A. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Toward a CRISPR-based mouse model of Vhl -deficient clear cell kidney cancer: Initial experience and lessons learned
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-10-04 , DOI: 10.1073/pnas.2408549121
Laura A. Stransky, Wenhua Gao, Laura S. Schmidt, Kevin Bi, Christopher J. Ricketts, Vijyendra Ramesh, Amy James, Simone Difilippantonio, Lilia Ileva, Joseph D. Kalen, Baktiar Karim, Albert Jeon, Tamara Morgan, Andrew C. Warner, Sevilay Turan, Joanne Unite, Bao Tran, Sulbha Choudhari, Yongmei Zhao, Douglas E. Linn, Changhong Yun, Sripriya Dhandapani, Vaishali Parab, Elaine M. Pinheiro, Nicole Morris, Lixia He, Sean M. Vigeant, Jean-Christophe Pignon, Maura Sticco-Ivins, Sabina Signoretti, Eliezer M. Van Allen, W. Marston Linehan, William G. Kaelin

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 Pax 8) 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.

更新日期：2024-10-04

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南