Independent signaling pathways provide a fail-safe mechanism to prevent tumorigenesis

Abstract

Controlled signaling activity is vital for normal tissue homeostasis and oncogenic signaling activation facilitates tumorigenesis. Here we use single-cell transcriptomics to investigate the effects of pro-proliferative signaling on epithelial homeostasis using the Drosophila follicle cell lineage. Notably, EGFR-Ras overactivation induces cell cycle defects by activating the transcription factors Pointed and E2f1 and impedes differentiation. Hh signaling simultaneously promotes an undifferentiated state and induces differentiation via activation of EMT-associated transcription factors zfh1 and Mef2. As a result, overactivation of Hh signaling generates a transcriptional hybrid state comparable to epithelial-mesenchymal-transition. Co-overactivation of Hh signaling with EGFR-Ras signaling blocks differentiation and induces key characteristics of tumor cells including a loss of tissue architecture caused by reduced expression of cell adhesion molecules, sustained proliferation and an evasion of cell cycle checkpoints. These findings provide new insight into how non-interacting signaling pathways converge at the transcriptional level to prevent malignant cell behavior. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/640798v2_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@762724org.highwire.dtl.DTLVardef@103d1a6org.highwire.dtl.DTLVardef@1b90caforg.highwire.dtl.DTLVardef@1eff5a4_HPS_FORMAT_FIGEXP M_FIG C_FIG