Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation.
Wilms tumor (WT) is a genetically heterogeneous childhood kidney tumor. Several genetic alterations have been identified in WT patients, including inactivating mutations in WT1 and loss of heterozygosity or loss of imprinting at 11p15, which results in biallelic expression of IGF2. However, the mechanisms by which one or a combination of genetic alterations results in tumorigenesis has remained challenging to determine, given the lack of a mouse model of WT. Here, we engineered mice to sustain mosaic, somatic ablation of Wt1 and constitutional Igf2 upregulation, mimicking a subset of human tumors. Mice with this combination of genetic alterations developed tumors at an early age. Mechanistically, Wt1 ablation blocked mesenchyme differentiation, and increased Igf2 expression upregulated ERK1/2 phosphorylation. Importantly, a subset of human tumors similarly displayed upregulation of ERK1/2 phosphorylation, which suggests ERK signaling might contribute to WT development. Thus, we have generated a biologically relevant mouse model of WT and defined one combination of driver alterations for WT. This mouse model will provide a powerful tool to study the biology of WT initiation and progression and to investigate therapeutic strategies for cancers with IGF pathway dysregulation.
Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Qianghua
Q
Hu
Fei
F
Gao
Weihua
W
Tian
E Cristy
EC
Ruteshouser
Yaqing
Y
Wang
Alexander
A
Lazar
John
J
Stewart
Louise C
LC
Strong
Richard R
RR
Behringer
Vicki
V
Huff
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D016162:Genes, Wilms Tumor; D005818:Genetic Engineering; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D009030:Mosaicism; D009368:Neoplasm Transplantation; D011247:Pregnancy; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
D017931:DNA Primers; C513121:IGF2 protein, mouse; D007335:Insulin-Like Growth Factor II; D048049:Extracellular Signal-Regulated MAP Kinases