The proteomic landscape of pancreatic ductal adenocarcinoma liver metastases identifies molecular subtypes and associations with clinical response A C

Henry C.H. Law, Dragana Lagundzin, Emalie J. Clement, Fangfang Qiao, Zachary S. Wagner, Kimiko L. Krieger, Diane Costanzo-Garvey, Thomas C. Caffrey, Jean L. Grem, Dominick J. DiMaio, Paul M. Grandgenett, Leah M. Cook, Kurt W. Fisher, Fang Yu, Michael A. Hollingsworth, Nicholas T. Woods

Research output: Contribution to journalArticle

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC. Experimental Design: A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics. PDAC subtypes were identified by principal component analysis based on protein expression profiling. Proteomic subtypes were further characterized by the associated clinical information, including but not limited to survival analysis, drug treatment response, and smoking and drinking status. Results: Over 3,960 proteins were identified and used to delineate four distinct PDAC microenvironment subtypes: (i) metabolic; (ii) progenitor-like; (iii) proliferative; and (iv) inflammatory. PDAC risk factors of alcohol and tobacco consumption correlate with subtype classifications. Enhanced survival is observed in FOLFIRINOX treated metabolic and progenitor-like subtypes compared with the proliferative and inflammatory subtypes. In addition, TYMP, PDCD6IP, ERAP1, and STMN showed significant association with patient survival in a subtype-specific manner. Gemcitabine-induced alterations in the proteome identify proteins, such as serine hydroxymethyltransferase 1, associated with drug resistance. Conclusions: These data demonstrate that proteomic analysis of clinical PDAC liver metastases can identify molecular signatures unique to disease subtypes and point to opportunities for therapeutic development to improve the treatment of PDAC.

Original languageEnglish (US)
Pages (from-to)1065-1076
Number of pages12
JournalClinical Cancer Research
Volume26
Issue number5
DOIs
StatePublished - Mar 1 2020

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Law, H. C. H., Lagundzin, D., Clement, E. J., Qiao, F., Wagner, Z. S., Krieger, K. L., Costanzo-Garvey, D., Caffrey, T. C., Grem, J. L., DiMaio, D. J., Grandgenett, P. M., Cook, L. M., Fisher, K. W., Yu, F., Hollingsworth, M. A., & Woods, N. T. (2020). The proteomic landscape of pancreatic ductal adenocarcinoma liver metastases identifies molecular subtypes and associations with clinical response A C. Clinical Cancer Research, 26(5), 1065-1076. https://doi.org/10.1158/1078-0432.CCR-19-1496