Hh and EGFR-Ras signaling promote distinct steps of tumor progression in the Drosophila follicle epithelium

TL;DR

This study explores how two signaling pathways, Hh and EGFR-Ras, contribute to tumor progression in fruit fly ovarian cells by affecting cell differentiation and tissue structure.

Contribution

The study reveals how Hh and EGFR-Ras signaling pathways converge at the transcriptional level to drive tumor-like growth in Drosophila follicle cells.

Findings

Hedgehog signaling promotes an undifferentiated state and induces partial epithelial-mesenchymal transition.

EGFR-Ras overactivation causes cell cycle defects and blocks differentiation.

Combined pathway overactivation leads to tumor-like growth with loss of tissue architecture and host lifespan reduction.

Abstract

Controlled signaling activity is vital for normal tissue homeostasis and oncogenic signaling activation facilitates tumorigenesis. Here, we combine single-cell transcriptomics with in-depth genetic and imaging analysis to investigate the role of the EGFR-Ras and Hedgehog signaling pathways in homeostasis of the Drosophila follicle stem cell lineage. We find that Hedgehog signaling simultaneously promotes an undifferentiated state and induces differentiation via activation of the epithelial-mesenchymal-transition associated transcription factor Zfh1. Overactivation of Hedgehog signaling generates a mixed transcriptional state comparable to partial epithelial-mesenchymal-transition. EGFR-Ras overactivation induces cell cycle defects by activating the transcription factors Pointed and E2f1 and impedes differentiation. Overactivation of both pathways blocks differentiation and induces tumor-like growth where follicle cells exhibit a loss of tissue architecture, sustained proliferation and a reduced lifespan of the host. These findings provide new insight into how signaling pathways converge at the transcriptional level to prevent malignant cell behavior.

Aberrant signaling pathway activation is a key driver of tumorigenesis. Using single-cell RNA sequencing, the authors unravel how EGFR-Ras and Hedgehog signaling promote distinct steps of tumor progression in a Drosophila ovarian tumor model.

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