ABSTRACT
Several oncogenes induce untimely entry into S phase and alter replication timing and progression, thereby generating replicative stress, a well-known source of genomic instability and a hallmark of cancer. Using an epithelial model in Drosophila, we show that the RAS oncogene, which triggers G1/S transition, induces DNA damage and, at the same time, silences the DNA damage response pathway. RAS compromises ATR-mediated phosphorylation of the histone variant H2Av and ATR-mediated cell-cycle arrest in G2 and blocks, through ERK, Dp53-dependent induction of cell death. We found that ERK is also activated in normal tissues by an exogenous source of damage and that this activation is necessary to dampen the pro-apoptotic role of Dp53. We exploit the pro-survival role of ERK activation upon endogenous and exogenous sources of DNA damage to present evidence that its genetic or chemical inhibition can be used as a therapeutic opportunity to selectively eliminate RAS-malignant tissues.
Subject(s)
Apoptosis/drug effects , DNA Damage/genetics , Drosophila Proteins/metabolism , Drosophila/genetics , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Eye Neoplasms/therapy , Genes, ras , Tumor Suppressor Protein p53/metabolism , Animals , Animals, Genetically Modified , Apoptosis/genetics , Apoptosis/radiation effects , Caspases , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , DNA Damage/drug effects , DNA Damage/radiation effects , Drosophila/metabolism , Drosophila/radiation effects , Drosophila Proteins/chemistry , Drosophila Proteins/genetics , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Eye Neoplasms/drug therapy , Eye Neoplasms/genetics , Eye Neoplasms/metabolism , G2 Phase Cell Cycle Checkpoints/genetics , G2 Phase Cell Cycle Checkpoints/radiation effects , Genomic Instability , Histones/chemistry , Histones/metabolism , Larva/genetics , Larva/metabolism , Larva/radiation effects , Mutation , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , S Phase/genetics , S Phase/radiation effects , Signal Transduction , Tumor Suppressor Protein p53/geneticsABSTRACT
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.
