Vanderbilt University Medical Center, United States
Background: Despite research efforts, metastatic cancers and relapse remain the primary cause of cancer related deaths. In renal cell carcinoma (RCC), metastasis is present in one-third of patients at the time of diagnosis, and one-third of patients who initially present with locally advanced disease eventually develop local or distant recurrence following tumor resection, highlighting the need for new RCC therapies and further insight into the metastatic process.
Methods: Patient biopsies from 181 clear cell RCC (ccRCC) patients were evaluated using immunohistochemistry, bulk RNA sequencing, and whole exome sequencing. These results were integrated with clinical data for each patient. CRISPR-Cas9 was used to knock-out SETD2 in mouse models of kidney cancer.
Results: Using patient biopsies, we found that patients with more epithelial tumors have a significantly lower risk of recurrence. Tumors that had a mesenchymal protein signature had significantly increased macrophage infiltration, which was significantly associated with a higher stage at diagnosis and worse overall survival, suggesting that macrophages may play an important role in EMT and metastasis in ccRCC. Whole exome sequencing of these patient samples revealed that mutational loss of SETD2, a histone methyltransferase that is lost in ~20% of RCC patients, correlated strongly with increased macrophage infiltration within the primary tumor and was necessary for the correlation between macrophages and EMT. SETD2 loss in syngeneic kidney cancer mouse models confirmed that SETD2 loss within tumor cells resulted in increased EMT, macrophages within the primary tumor microenvironment (TME), and spontaneous metastasis, further supporting the role of macrophages in promoting metastasis in the absence of SETD2.
Conclusions: Our studies reveal that SETD2 loss within the tumor cells leads to the recruitment of macrophages to the TME as well as increased spontaneous metastases. Current studies are being done to understand how this process may be targeted for more efficacious therapies for metastatic patients.
