Dr Arner on the Role of SETD2 Loss in Tumor Growth and Metastasis in ccRCC

Emily Arner, PhD, post-doctoral research fellow, Division of Hematology/Oncology, Vanderbilt University Medical Center, discusses research on the role of SET domain-containing protein 2 (SETD2) loss in metastatic clear cell renal cell carcinoma (ccRCC), highlighting its impact on the tumor microenvironment and metastasis.

Loss of the histone methyltransferase SET domain-containing protein 2 (SETD2) is common in ccRCC, occurring in about 20% of patients, Arner states. Although SETD2 is known to play a role in the tumor microenvironment, its potential role in tumor growth and metastasis requires further research, Arner explains.

A study investigating the role of SETD2 loss in ccRCC was conducted to address this question. Utilizing patient biopsies, the research found that tumors with a mesenchymal protein signature, indicative of epithelial-mesenchymal transition (EMT), exhibited increased macrophage infiltration, Arner details.

The observed correlation between decreased E-cadherin expression levels and increased metastasis underscores the significance of epithelial characteristics in tumor aggressiveness and highlights the role of this adhesion protein in inhibiting tumor spread, Arner adds. Importantly, this association with macrophage infiltration was linked to higher disease stage at diagnosis and worse overall survival, suggesting a potential role of macrophages in promoting metastasis in ccRCC, she emphasizes. Although immune cells are typically regarded as tumor suppressors, the pro-tumorigenic role of macrophages in ccRCC suggests a more nuanced understanding of their function within the tumor microenvironment, Arner explains.

Whole exome sequencing revealed that mutational loss of SETD2 was correlated with increased macrophage infiltration within the primary tumor, Arner continues. Additionally, SETD2 loss was found to be necessary for the correlation between macrophages and EMT. Further confirmation was obtained through syngeneic kidney cancer mouse models where mutational 

 loss within tumor cells led to increased EMT, macrophage infiltration, and spontaneous metastasis, Arner notes.

Based on these findings, investigators highlight the critical role of SETD2 loss in ccRCC progression and metastasis by modulating the tumor microenvironment, particularly through the recruitment of macrophages, Arner says. The study suggests that targeting this process could lead to more efficacious therapies for metastatic ccRCC patients. Ongoing research is focused on understanding the mechanisms underlying this process and identifying potential therapeutic targets to intervene in metastatic ccRCC, Arner concludes.

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Emily Arner, PhD, discusses research on the role of SETD2 loss in metastatic clear cell renal cell carcinoma ccRCC.

Emily Arner, PhD

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Dr Arner on the Role of SETD2 Loss in Tumor Growth and Metastasis in ccRCC