Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

Richard A. Moffitt, Raoud Marayati, Elizabeth L. Flate, Keith E. Volmar, S. Gabriela Herrera Loeza, Katherine A. Hoadley, Naim U. Rashid, Lindsay A. Williams, Samuel C. Eaton, Alexander H. Chung, Jadwiga K. Smyla, Judy M. Anderson, Hong Jin Kim, David J. Bentrem, Mark S. Talamonti, Christine A. Iacobuzio-Donahue, Michael A. Hollingsworth, Jen Jen Yeh

Research output: Contribution to journalArticlepeer-review

784 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.

Original languageEnglish (US)
Pages (from-to)1168-1178
Number of pages11
JournalNature Genetics
Volume47
Issue number10
DOIs
StatePublished - Sep 29 2015

Bibliographical note

Funding Information:
We thank the University of North Carolina (UNC) Tissue Procurement, Translational Pathology Laboratory, Animal Studies, Animal Histopathology, and Center for Gastrointestinal Biology and Disease Histopathology core facilities (NIH grant P30-DK034897), the PDX Program and Department of Pharmacology for tremendous technical support. We thank the patients and their families who generously donated their samples to research and in particular to the University of Nebraska Medical Center Rapid Autopsy Pancreatic Program and the Johns Hopkins Gastrointestinal Cancer Rapid Medical Donation Program. This work was partially supported by grant R01-CA140424 from the US National Institutes of Health (NIH) (J.J.Y.), the Kimmel Foundation (J.J.Y.), the American College of Surgeons (J.J.Y.), the University Cancer Research Fund (J.J.Y.) and UNC Lineberger Comprehensive Cancer Center Postdoctoral Training Grant T32-CA009156 from the US NIH (R.A.M.).

Publisher Copyright:
© 2015 Nature America, Inc.

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