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<p>Inflammation triggers systemic growth restrictions, a process well characterised in tumour cachexia. Whether inflammatory tissue damage also induces growth restrictions, and how regenerating tissue overcome them, is less explored. Using a tissue damage model in <i>Drosophila</i>, we identify metabolic and signaling adaptations that both induce and bypass systemic growth restrictions. Expression of <i>eiger</i>, the <i>Drosophila</i> TNF-α homolog, in imaginal discs causes systemic insulin restriction and insulin resistance, reducing protein translation and proliferation in peripheral tissues. Regenerating cells overcome this by upregulating Pdk1, which is necessary and sufficient to promote protein translation via an Insulin/Akt-independent mechanism. JAK/STAT acts upstream to elevate Pdk1, defining a JAK/STAT-Pdk1-S6K axis essential for regenerative proliferation. Regenerating cells also upregulate amino acid transporters and rely on mTORC1. Similar signatures in Ras<sup>V12</sup>, scrib tumors indicate that tumors co-opt these pathways to sustain growth under insulin restriction. This physiological program thus integrates systemic nutrient mobilization and local metabolic reprogramming, with implications for tissue repair but also pathologies, such as chronic wounds and cancer.</p>

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A JAK/STAT-Pdk1-S6K axis bypasses systemic growth restrictions to promote regeneration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月6日

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  • Ananthakrishnan Vijayakumar Maya,
  • Lena Neuhaus,
  • Liyne Nogay,
  • Aakriti Singh,
  • Lara Heckmann,
  • Isabelle Grass,
  • Jörg Büscher,
  • Katrin Kierdorf,
  • Anne-Kathrin Classen

摘要

Inflammation triggers systemic growth restrictions, a process well characterised in tumour cachexia. Whether inflammatory tissue damage also induces growth restrictions, and how regenerating tissue overcome them, is less explored. Using a tissue damage model in Drosophila, we identify metabolic and signaling adaptations that both induce and bypass systemic growth restrictions. Expression of eiger, the Drosophila TNF-α homolog, in imaginal discs causes systemic insulin restriction and insulin resistance, reducing protein translation and proliferation in peripheral tissues. Regenerating cells overcome this by upregulating Pdk1, which is necessary and sufficient to promote protein translation via an Insulin/Akt-independent mechanism. JAK/STAT acts upstream to elevate Pdk1, defining a JAK/STAT-Pdk1-S6K axis essential for regenerative proliferation. Regenerating cells also upregulate amino acid transporters and rely on mTORC1. Similar signatures in RasV12, scrib tumors indicate that tumors co-opt these pathways to sustain growth under insulin restriction. This physiological program thus integrates systemic nutrient mobilization and local metabolic reprogramming, with implications for tissue repair but also pathologies, such as chronic wounds and cancer.