MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma.

Abstract

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 multifluorescent 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 amplification 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 findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically 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.This article is highlighted in the In This Issue feature, p. 275.

• Authors: Ravikanth Maddipati, Robert J Norgard, Timour Baslan, Komal S Rathi, Amy Zhang, Asal Saeid, Taku Higashihara, Feng Wu, Angad Kumar, Valli Annamalai, Saurav Bhattacharya, Pichai Raman, Christian A Adkisson, Jason R Pitarresi, Maximilian D Wengyn, Taiji Yamazoe, Jinyang Li, David Balli, Michael J LaRiviere, Tuong-Vi C Ngo, Ian W Folkert, Ian D Millstein, Jonathan Bermeo, Erica L Carpenter, John C McAuliffe, Maja H Oktay, Rolf A Brekken, Scott W Lowe, Christine A Iacobuzio-Donahue, Faiyaz Notta, Ben Z Stanger
• Journal: Cancer discovery (Cancer Discov) Vol. 12 Issue 2 Pg. 542-561 (Feb 2022) ISSN: 2159-8290 [Electronic] United States
• PMID: 34551968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Topics

• Adenocarcinoma (genetics, secondary)
• Animals
• Carcinoma, Pancreatic Ductal (genetics, secondary)
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Genes, myc
• Humans
• Mice
• Neoplasm Metastasis
• Pancreatic Neoplasms (genetics, pathology)