New syngeneic inflammatory-related lung cancer metastatic model harboring double KRAS/WWOX alterations.
New mouse models with specific drivers of genetic alterations are needed for preclinical studies. Herein, we created and characterized at the genetic level a new syngeneic model for lung cancer and metastasis in Balb-c mice. Tumor cell lines were obtained from a silica-mediated airway chronic inflammation that promotes tumorigenesis when combined with low doses of N-nitrosodimethylamine, a tobacco smoke carcinogen. Orthotopic transplantation of these cells induced lung adenocarcinomas, and their intracardiac injection led to prominent colonization of various organs (bone, lung, liver and brain). Driver gene alterations included a mutation in the codon 12 of KRAS (G-A transition), accompanied by a homozygous deletion of the WW domain-containing oxidoreductase (WWOX) gene. The mutant form of WWOX lacked exons 5-8 and displayed reduced protein expression level and activity. WWOX gene restoration decreased the in vitro and in vivo tumorigenicity, confirming the tumor suppressor function of this gene in this particular model. Interestingly, we found that cells displayed remarkable sphere formation ability with expression of specific lung cancer stem cell markers. Study of non-small-cell lung cancer patient cohorts demonstrated a deletion of WWOX in 30% of cases, with significant reduction in protein levels as compared to normal tissues. Overall, our new syngeneic mouse model provides a most valuable tool to study lung cancer metastasis in balb-c mice background and highlights the importance of WWOX deletion in lung carcinogenesis.
Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Anne-Marie
AM
Bleau
Javier
J
Freire
María José
MJ
Pajares
Isabel
I
Zudaire
Iker
I
Anton
Estanislao
E
Nistal-Villán
Miriam
M
Redrado
Caroli Na
CN
Zandueta
Irati
I
Garmendia
Daniel
D
Ajona
David
D
Blanco
Ruben
R
Pio
Fernando
F
Lecanda
Alfonso
A
Calvo
Luis M
LM
Montuenga
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000556:secondary; D049109:Cell Proliferation; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
WWOX; lung cancer; metastasis; mouse model