Identification of a pyruvate-to-lactate signature in pancreatic intraductal papillary mucinous neoplasms

Alan R. Penheiter, Dinesh K. Deelchand, Emily Kittelson, Sibel Erdogan Damgard, Stephen J. Murphy, Daniel R. O'Brien, William R. Bamlet, Marie R. Passow, Thomas C. Smyrk, Fergus J. Couch, George Vasmatzis, John D. Port, Małgorzata Marjańska, Stephanie K. Carlson

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Objective We used transcriptomic profiling and immunohistochemistry (IHC) to search for a functional imaging strategy to resolve common problems with morphological imaging of cystic neoplasms and benign cystic lesions of the pancreas. Methods Resected pancreatic cancer (n = 21) and normal pancreas were laser-capture micro-dissected, and transcripts were quantified by RNAseq. Functional imaging targets were validated at the protein level by IHC on a pancreatic adenocarcinoma tissue microarray and a newly created tissue microarray of resected intraductal papillary mucinous neoplasms (IPMNs) and IPMN-associated adenocarcinomas. Results Genes encoding proteins responsible for cellular import of pyruvate, export of lactate, and conversion of pyruvate to lactate were highly upregulated in pancreatic adenocarcinoma compared to normal pancreas. Strong expression of MCT4 and LDHA was observed by IHC in >90% of adenocarcinoma specimens. In IPMNs, the pyruvate-to-lactate signature was significantly elevated in high grade dysplasia (HGD) and IPMN-associated adenocarcinoma. Additionally, cores containing HGD and/or adenocarcinoma exhibited a higher number of peri-lesional stromal cells and a significant increase in peri-lesional stromal cell staining of LDHA and MCT4. Interestingly, the pyruvate-to-lactate signature was significantly upregulated in cores containing only low grade dysplasia (LGD) from patients with histologically confirmed IPMN-associated adenocarcinoma versus LGD cores from patients with non-invasive IPMNs. Conclusion Our results suggest prospective studies with hyperpolarized [1–13C]-pyruvate magnetic resonance spectroscopic imaging are warranted. If these IHC results translate to functional imaging findings, a positive pyruvate-to-lactate imaging signature might be a risk factor for invasion that would warrant resection of IPMNs in the absence of other worrisome features.

Original languageEnglish (US)
Pages (from-to)46-53
Number of pages8
JournalPancreatology
Volume18
Issue number1
DOIs
StatePublished - Jan 2018

Bibliographical note

Funding Information:
SKC acknowledges the support of a generous benefactor gift from Ted L. Shabert , an award from the National Cancer Institute ( P50CA102701 [Mayo Clinic SPORE in Pancreatic Cancer]), the Minnesota Partnership for Biotechnology and Medical Genomics ( MNP #16.37 ), the Imaging Biomarker Program within the Center for Individualized Medicine at Mayo Clinic , the Mayo Clinic Center for Clinical and Translational Science (CCaTS) ( UL1TR000135 ), and an award from the Fifth District Fraternal Order of Eagles Cancer Research Fund . We would like to thank Anthony J. Blahnik, LouAnn A. Gross, Sarah N. Tangen, Eileen L. Holicky, Lorna K. Lubinski, Nathan G. Faiman, Peggy M. Gosse Rahnenfuehrer, and Stephen N. Hart for their technical expertise and Gloria M. Petersen for helpful discussion. We would also like to thank the Mayo Clinic Advanced Genomic Technology Center Gene Expression Core. We acknowledge the assistance of Sonia Watson, PhD, in editing and submission of the manuscript. DKD, EK, and MM acknowledge support of the NIH grant P41 EB015894 and the W.M. Keck Foundation . The authors have no other conflicts of interest to disclose.

Keywords

  • Hyperpolarized
  • IPMN
  • Magnetic resonance spectroscopy
  • Pancreatic adenocarcinoma
  • Pyruvate

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