# Genetic dissection of signalling pathways that mediate iron-related tumor growth in a Drosophila model

## TL;DR

This study uses fruit flies to show how excess iron and a transporter called dZIP13 influence tumor growth and gene regulation in cancer.

## Contribution

The study reveals a novel tumor-suppressor role for dZIP13 and molecular mechanisms linking iron to cancer progression.

## Key findings

- Reduced dZIP13 leads to cytosolic iron accumulation and worsened cancer-like traits.
- Iron-dependent DNA demethylation and histone modification activate the JAK/STAT pathway, promoting tumor growth.
- Iron overload increases tumor invasiveness and hemocyte recruitment via epigenetic changes.

## Abstract

Iron dyshomeostasis is associated with various cancers. Here we explore the underlying mechanisms through which iron promotes tumor growth and metastasis using a Drosophila cancer model. In this model, cells iin the eye-antennal imaginal disc co-express oncogenic Raf gain-of-function and Scribbled loss-of-function mutants, leading to tumor formation. First, we show that dietary iron overload enhances tumor growth, invasiveness and mobility of cancer cells, whereas iron chelation suppresses these phenotypes. Consistently, RNA interference (RNAi)-mediated knockdown of dZIP13, a zinc transporter that transports iron into the secretory pathway, results in cytosolic iron accumulation and exacerbates the cancer-like phenotypes. Second, we show that the activity of a ten-eleven translocation DNA dioxygenase (TET), which enables DNA demethylation, correlates with cellular iron bioavailability, consistent with the known requirement of iron in the catalytic site of this enzyme. Third, we show that the TET enzyme transcriptionally regulates a histone methylase responsible for the H3K27me3 epigenetic mark. Fourth, we demonstrate that the iron-dependent DNA demethylation and subsequent histone trimethylation events activate the JAK/STAT signalling pathway, which promotes tumorigenesis, including the recruitment and proliferation of hemocytes to the malignant tissue. These findings reveal a novel tumor-suppressor function for dZIP13, while providing molecular mechanisms for iron-mediated tumor progression.

Iron is an essential nutrient, but too much iron can be harmful and is often linked to cancer. In this study, we used fruit flies (Drosophila) to investigate how excess iron contributes to tumor growth. We found that altering the expression of a metal transporter called dZIP13, which controls how iron is distributed inside cells, changes the amount of iron in specific cellular compartments and affects tumor behavior. When dZIP13 function was reduced, iron accumulated in the wrong place, causing tumors to grow faster and invade nearby tissues. We also discovered that this process changes how certain genes are regulated through chemical marks on DNA and histones, activating a signalling pathway that promotes tumor growth and recruits immune-like cells to the tumor. Our work reveals how a single gene that controls iron distribution can influence gene regulation during cancer progression.