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Published on: October 6, 2016
Drosophila as Model System to Study Ras-Mediated Oncogenesis: The Case of the Tensin Family of Proteins
Ana Martínez-Abarca Millán1, Jennifer Soler Beatty1, Andrea Valencia Expósito1
1Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/CSIC/JA, Ctra Utrera Km1, 41013 Sevilla, Spain.
Abstract:
Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, tissue growth induced by oncogenic Ras is restrained by the induction of cellular senescence, and additional mutations are required to induce tumor progression. Therefore, identifying cooperating cancer genes is of paramount importance. Recently, the tensin family of focal adhesion proteins, TNS1-4, have emerged as regulators of carcinogenesis, yet their role in cancer appears somewhat controversial. Around 90% of human cancers are of epithelial origin. We have used the Drosophila wing imaginal disc epithelium as a model system to gain insight into the roles of two orthologs of human TNS2 and 4, blistery (by) and PVRAP, in epithelial cancer progression. We have generated null mutations in PVRAP and found that, as is the case for by and mammalian tensins, PVRAP mutants are viable. We have also found that elimination of either PVRAP or by potentiates Ras-mediated wing disc hyperplasia. Furthermore, our results have unraveled a mechanism by which tensins may limit Ras oncogenic capacity, the regulation of cell shape and growth. These results demonstrate that Drosophila tensins behave as suppressors of Ras-driven tissue hyperplasia, suggesting that the roles of tensins as modulators of cancer progression might be evolutionarily conserved.
Insights
Ras mutations drive cancer, but cellular senescence often halts tumor growth. This study reveals that Drosophila tensins, blistery (by) and PVRAP, act as tumor suppressors by limiting Ras-driven tissue overgrowth, suggesting conserved roles in cancer progression.
Area of Science:
- Cellular Biology
- Developmental Biology
- Cancer Research
Background:
- Oncogenic Ras mutations are implicated in approximately 30% of human cancers.
- Ras-driven tissue growth is often restrained by cellular senescence, requiring cooperating mutations for tumor progression.
- The tensin family (TNS1-4) proteins are focal adhesion proteins with emerging, yet debated, roles in carcinogenesis.
Purpose of the Study:
- To investigate the roles of Drosophila tensin orthologs, blistery (by) and PVRAP (orthologs of human TNS2 and TNS4), in epithelial cancer progression.
- To understand the mechanism by which tensins may limit Ras oncogenic capacity in epithelial tissues.
Main Methods:
- Utilized the Drosophila wing imaginal disc epithelium as a model system for epithelial cancer research.
- Generated null mutations in PVRAP.
- Assessed the impact of PVRAP and by mutations on Ras-mediated wing disc hyperplasia.
Main Results:
- Generated viable PVRAP null mutants, similar to by and mammalian tensins.
- Elimination of either PVRAP or by potentiated Ras-mediated wing disc hyperplasia.
- Unraveled a mechanism where tensins regulate cell shape and growth, thereby limiting Ras oncogenic capacity.
Conclusions:
- Drosophila tensins, PVRAP and by, function as suppressors of Ras-driven tissue hyperplasia.
- Tensins' roles as modulators of cancer progression, particularly in epithelial cancers, appear to be evolutionarily conserved.
- Regulation of cell shape and growth by tensins is a key mechanism limiting oncogenic Ras activity.
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