# Toll signaling controls stem cell proliferation in intestinal regeneration and tumorigenesis

## TL;DR

The study shows that Toll signaling in fruit flies controls intestinal stem cell growth and tumor formation through a non-immune mechanism involving PI3K/Akt.

## Contribution

The paper reveals a novel non-immune role of Toll signaling in regulating stem cell activity and tumorigenesis via PI3K/Akt.

## Key findings

- Toll signaling directly regulates PI3K and Akt to control intestinal stem cell proliferation.
- The Jumu/Spz/Toll pathway drives both tissue regeneration and tumor growth in the intestine.
- PI3K/Akt functions downstream of Toll in this regulatory cascade.

## Abstract

The Drosophila Toll/NF-κB pathway has been extensively studied for its roles in innate immunity and embryonic development. Nevertheless, the regulatory mechanisms underlying Spz/Toll signaling in non-immune contexts remain poorly understood. Here, we demonstrate a critical role for Toll in regulating intestinal stem cell activity through direct transcriptional control of PI3K and Akt in an insulin-independent manner. Time-series transcriptomic analysis of intestinal damage and repair responses reveals that the stress-responsive factor Jumu regulates Spz expression to activate Toll signaling. Disruption of the Jumu/Spz/Toll cascade or PI3K/Akt signaling impairs intestinal regeneration and suppresses tumor growth, and epistasis analysis confirms that PI3K/Akt functions downstream of Toll. Our findings elucidate an autocrine Spz/Toll-mediated mechanism that drives stem cell function via the PI3K/Akt pathway during tissue homeostasis and uncover a critical non-immune role of Toll signaling in both physiological and pathological contexts.

The Drosophila Jumu/Spz/Toll cascade promotes intestinal stem cell proliferation by directly inducing PI3K/Akt transcription. This autocrine non-immune mechanism promotes both physiological tissue regeneration and pathological tumor growth.

Toll signaling promotes ISC proliferation via transcriptionally regulating PI3K and Akt.Jumu induces Spz expression in ISCs to activate the Toll signaling pathway.The Jumu/Spz/Toll cascade drives both physiological tissue regeneration and pathological tumor growth.

Toll signaling promotes ISC proliferation via transcriptionally regulating PI3K and Akt.

Jumu induces Spz expression in ISCs to activate the Toll signaling pathway.

The Jumu/Spz/Toll cascade drives both physiological tissue regeneration and pathological tumor growth.

The Drosophila Jumu/Spz/Toll cascade promotes intestinal stem cell proliferation by directly inducing PI3K/Akt transcription. This autocrine non-immune mechanism promotes both physiological tissue regeneration and pathological tumor growth.