In vivo interaction screening reveals liver-derived constraints to metastasis
Costanza Borrelli1, Morgan Roberts1, Davide Eletto1
1Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Nature
|July 24, 2024
Summary
Researchers discovered that the liver protein plexin B2 is crucial for cancer cells to colonize the liver. Blocking this interaction prevents liver metastasis, offering a new therapeutic strategy for preventing secondary tumors.
Area of Science:
- Cancer Biology
- Metastasis Research
- Hepatology
Background:
- Only a small fraction of disseminated tumor cells successfully form overt metastases, indicating significant environmental constraints.
- The host factors that control metastatic seeding and liver colonization remain largely unknown.
- Understanding host-tumor interactions is critical for developing effective anti-metastasis therapies.
Purpose of the Study:
- To systematically investigate host factors, specifically hepatocyte interactions, that regulate metastatic seeding in the liver.
- To identify novel host-derived regulators of liver colonization in colorectal cancer, pancreatic cancer, and melanoma.
- To elucidate the molecular mechanisms underlying liver metastasis and explore potential therapeutic targets.
Main Methods:
- Development of an in vivo CRISPR activation screen combining transposon technology and fluorescence niche labeling.
- Systematic investigation of interactions between hepatocytes and metastatic cells in syngeneic mouse models.
- Dissection of the molecular pathway involving plexin B2, semaphorins, and KLF4 in tumor cell adaptation.
Main Results:
- Plexin B2 was identified as a critical host-derived regulator of liver colonization for colorectal cancer, pancreatic cancer, and melanoma.
- Plexin B2 interacts with class IV semaphorins on tumor cells, upregulating KLF4 and promoting epithelial traits necessary for colonization.
- Blocking the plexin B2-semaphorin axis significantly abolished liver metastatic colonization in preclinical models.
Conclusions:
- Liver parenchymal signals are essential for the initial seeding and adaptation of disseminated tumor cells.
- Epithelialization, driven by the plexin B2-semaphorin-KLF4 axis, is required for colorectal cancer (CRC) metastasis adaptation to the liver.
- Targeting the plexin B2-semaphorin axis presents a promising therapeutic strategy for preventing hepatic metastases.
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