MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma

The degree of metastatic disease varies widely among patients with cancer and affects clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifl uorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC)-a tumor type in which most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplifi cation or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor-associated macrophages, leading to greater bloodstream intravasation. Consistent with these fi ndings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifi cations specifi cally in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. SIGNIFICANCE: Here, we investigate metastatic variation seen clinically in patients with PDAC and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.

Automated summary

This study investigated the biological and functional differences driving metastasis in patients with PDAC using a mouse model. The findings revealed an association between the extent of metastasis and gene amplification or transcriptional upregulation of the MYC gene and its downstream targets. Functional experiments demonstrated that MYC promotes metastasis by recruiting tumor-associated macrophages. Further analysis showed that metastatic progression in human PDAC is associated with activation of MYC signaling pathways and MYC amplifications in metastatic patients specifically.