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.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Oct 04 [Epub]
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
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892., Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115., Animal Research Technical Support, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Small Animal Imaging Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., National Cancer Institute Center for Cancer Research, Sequencing Facility, Frederick National Laboratory for Cancer Research, Frederick, MD 21701., Advanced Biomedical and Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701., Quantitative Biosciences, Merck & Co., Inc., Boston, MA 02115., Pharmacokinetics, Merck & Co., Inc., Boston, MA 02115., Pharmacokinetics, Merck & Co., Inc., South San Francisco, CA 94080., Discovery Oncology Merck & Co., Inc., Boston, MA 02115., Laboratory of Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Harvard Medical School, Boston, MA 02115.