RRC ID 49226
Author Muzzopappa M, Murcia L, Milán M.
Title Feedback amplification loop drives malignant growth in epithelial tissues.
Journal Proc Natl Acad Sci U S A
Abstract 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-α 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.
Volume 114(35)
Pages E7291-E7300
Published 2017-8-29
DOI 10.1073/pnas.1701791114
PII 1701791114
PMID 28808034
PMC PMC5584413
MeSH Allografts Animals Animals, Genetically Modified / metabolism Apoptosis Carcinogenesis / metabolism Cell Polarity Cell Proliferation Cell Transformation, Neoplastic / metabolism Chromosomal Instability Drosophila Proteins / metabolism Drosophila Proteins / physiology Drosophila melanogaster / physiology Epithelium / metabolism Feedback, Physiological / physiology MAP Kinase Signaling System / genetics* MAP Kinase Signaling System / physiology* Membrane Proteins / metabolism Neoplasms / metabolism* Signal Transduction Tumor Microenvironment / physiology Tumor Necrosis Factor-alpha / metabolism ras Proteins / metabolism
IF 9.412
Times Cited 16