Modeling Tumor Progression by the Sequential Introduction of Genetic Alterations into the Genome of Human Normal Cells

被引:6
作者
Zecchin, Davide [1 ,2 ]
Arena, Sabrina [1 ,2 ]
Martini, Miriam [1 ,2 ]
Sassi, Francesco [1 ,2 ]
Pisacane, Alberto [2 ]
Di Nicolantonio, Federica [1 ,2 ]
Bardelli, Alberto [1 ,2 ,3 ]
机构
[1] Univ Turin, Dept Oncol, Turin, Italy
[2] IRC C Inst Canc Res Candiolo, Turin, Italy
[3] FIRC Inst Mol Oncol IFOM, Milan, Italy
关键词
tumor progression; transformation; oncogenes; tumor suppressor; BREAST-CANCER CELLS; MUTANT P53 ALLELES; K-RAS; INHIBITION; MUTATIONS; PATHWAY; PI3K; MICE; TRANSFORMATION; TUMORIGENESIS;
D O I
10.1002/humu.22234
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Cancer genomes display a complex blend of genetic lesions affecting oncogenes and tumor suppressor genes. Multiple modeling approaches indicate that 515 driver oncogenic events are required to achieve tumor progression in common epithelial cancers. In vitro, a lower number (23) of events is typically sufficient to achieve full transformation. We developed cellular models that closely resemble the occurrence of multiple genetic lesions to understand their role in tumor progression. Homologous recombination and transcriptional downregulation were used to recapitulate the co-occurrence of driver mutations targeting oncogenes and inactivation of tumor suppressor genes in human nontransformed epithelial cells. Knockdown of the tumor suppressor genes PTEN or RB1 was combined with mutagenic activation of individual oncogenes (EGFR, KRAS, BRAF, or PIK3CA), thus generating a combinatorial model. The simultaneous presence of oncogenic and tumor suppressive events resulted in distinct biochemical properties and anchorage-independent growth abilities. Notably, however, we found that even when up to four individual alterations were concomitantly present they were not sufficient to fully transform the target cells. Our results suggest that the close recapitulation of cancer lesions in not-transformed cells is essential to unveil their oncogenic potential and raise questions concerning the minimal requirements for neoplastic transformation of epithelial cells.
引用
收藏
页码:330 / 337
页数:8
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