MYC Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma
| Autor: | Maximilian D. Wengyn, Michael J. LaRiviere, Christian A Adkisson, Feng Wu, Asal Saeid, Scott W. Lowe, Taku Higashihara, Christine A. Iacobuzio-Donahue, David Balli, Ravikanth Maddipati, Saurav Bhattacharya, Jonathan Bermeo, Komal S. Rathi, Robert J. Norgard, Ian W. Folkert, Maja H. Oktay, Taiji Yamazoe, Amy Zhang, Jason R. Pitarresi, John C. McAuliffe, Ian D. Millstein, Tuong-Vi C Ngo, Timour Baslan, Jinyang Li, Ben Z. Stanger, Rolf A. Brekken, Angad Kumar, Erica L. Carpenter, Faiyaz Notta, Pichai Raman, Valli Annamalai |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
business.industry Intravasation Cancer medicine.disease Article 3. Good health Metastasis Transcriptome 03 medical and health sciences 0302 clinical medicine Oncology Downregulation and upregulation 030220 oncology & carcinogenesis Gene duplication Cancer research medicine Adenocarcinoma Signal transduction business 030304 developmental biology |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-20-1826 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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