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New syngeneic inflammatory‐related lung cancer metastatic model harboring double KRAS/WWOX alterations
Author(s) -
Bleau AnneMarie,
Freire Javier,
Pajares María José,
Zudaire Isabel,
Anton Iker,
NistalVillán Estanislao,
Redrado Miriam,
Zandueta Caroli na,
Garmendia Irati,
Ajona Daniel,
Blanco David,
Pio Ruben,
Lecanda Fernando,
Calvo Alfonso,
Montuenga Luis M.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28574
Subject(s) - wwox , cancer research , carcinogenesis , kras , lung cancer , metastasis , biology , cancer , tumor suppressor gene , medicine , pathology , colorectal cancer , suppressor
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.