Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 35, Pages E7291-E7300Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1701791114
Keywords
tumor microenvironment; chromosomal instability; epithelial tumor; Wingless; JNK
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Funding
- La Caixa
- Ministerio de Economia, Industria y Competitividad (MINECO) (Government of Spain) [SIGNAGROWTH-BFU2013-44485, INTERGROWTH-BFU2016-77587-P]
- Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
- Severo Ochoa Award of Excellence from MINECO
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Interactions between cells bearing oncogenic mutations and the surrounding microenvironment, and cooperation between clonally distinct cell populations, can contribute to the growth and malignancy of epithelial tumors. The genetic techniques available in Drosophila have contributed to identify important roles of the TNF-alpha ligand Eiger and mitogenic molecules in mediating these interactions during the early steps of tumor formation. Here we unravel the existence of a tumor-intrinsic-and microenvironment-independent-self-reinforcement mechanism that drives tumor initiation and growth in an Eiger-independent manner. This mechanism relies on cell interactions between two functionally distinct cell populations, and we present evidence that these cell populations are not necessarily genetically different. Tumor-specific and cell-autonomous activation of the tumorigenic JNK stress-activated pathway drives the expression of secreted signaling molecules and growth factors to delaminating cells, which nonautonomously promote proliferative growth of the partially transformed epithelial tissue. We present evidence that cross-feeding interactions between delaminating and nondelaminating cells increase each other's sizes and that these interactions can explain the unlimited growth potential of these tumors. Our results will open avenues toward our molecular understanding of those social cell interactions with a relevant function in tumor initiation in humans.
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