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Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue

Neha Diwanji1, Andreas Bergmann2

  • 1University of Massachusetts Medical School, Department of Molecular, Cell and Cancer Biology, 364 Plantation Street, LRB 419, Worcester, MA, 01605, USA.

Nature Communications
|July 21, 2020
PubMed

Insights

Tumor microenvironments recruit macrophages via reactive oxygen species (ROS) and JNK signaling, which upregulate matrix metalloproteinase 2 (Mmp2) to damage the basement membrane (BM), promoting tumor growth.

Area of Science:

  • Immunology
  • Developmental Biology
  • Cancer Biology

Background:

  • Macrophages are key immune cells in tumors, driving growth and metastasis.
  • Understanding macrophage recruitment to tumors is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the mechanisms of macrophage recruitment to overgrowing tissues using a Drosophila model.
  • To elucidate the role of the tumor microenvironment in macrophage activation.

Main Methods:

  • Utilized a Drosophila larval imaginal disc overgrowth model ('undead' model).
  • Analyzed the correlation between reactive oxygen species (ROS) generation, basement membrane (BM) damage, and macrophage infiltration.
  • Investigated the involvement of the stress kinase JNK and matrix metalloproteinase 2 (Mmp2).

Main Results:

  • Observed a correlation between ROS generation and BM damage in neoplastic, but not hyperplastic, overgrowth models.
  • Demonstrated that ROS and JNK signaling mediate Mmp2 accumulation, leading to BM damage.
  • Showed that BM damage is a critical step in recruiting macrophages to the tumor microenvironment.

Conclusions:

  • Macrophage recruitment to overgrowing tissues is a multi-step process.
  • ROS and JNK-mediated Mmp2 upregulation and subsequent BM damage are essential for macrophage recruitment.
  • These findings highlight the importance of the tumor microenvironment in macrophage activation and tumor progression.

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