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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Nur77 deficiency in mice accelerates tumor invasion and metastasis by facilitating TNFα secretion and lowering CSF-1R
Xiu-Ming Li1, Jing-Ru Wang1, Tong Shen1
1Pathology Center and Department of Pathology, Soochow University, Suzhou, China.
Abstract:
Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.
Insights
Nur77 deficiency accelerates tumor metastasis by promoting cancer cell epithelial-mesenchymal transition (EMT) and reducing inflammatory cell infiltration. Host Nur77 is crucial for antitumor immunity and inhibiting cancer spread.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Nur77 (nuclear receptor subfamily 4 group 1 member A2) is implicated in inflammation and immunity.
- Its role in the tumor microenvironment and cancer metastasis is not well understood.
Purpose of the Study:
- To investigate the function of Nur77 in regulating tumor metastasis and the tumor microenvironment.
- To elucidate the mechanisms by which Nur77 influences cancer cell behavior and immune cell infiltration.
Main Methods:
- Comparative analysis of tumor metastasis in Nur77 knockout (KO) and wild-type (WT) mice.
- Assessment of cancer cell epithelial-mesenchymal transition (EMT), migration, and invasion using conditioned media from Nur77 KO and WT macrophages.
- Involvement of TNF-α and CSF-1R in mediating Nur77's effects on cancer and immune cells.
Main Results:
- Nur77 deletion significantly enhanced tumor metastasis and promoted cancer cell EMT, migration, and invasion.
- Tumor necrosis factor-alpha (TNF-α) was essential for Nur77-deficient macrophage-conditioned media-induced cancer cell EMT and metastasis.
- Nur77 promotes CSF-1R expression, enhancing inflammatory cell migration, and its absence abrogated inflammatory cell infiltration in tumors.
Conclusions:
- Host Nur77 expression is critical for mounting an effective antitumor immune response.
- Nur77 acts as a tumor suppressor by inhibiting cancer cell metastasis through modulation of the tumor microenvironment and immune cell infiltration.
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