The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response

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.

Label-free proteomics reveals serum proteins whose levels differ between pancreatic ductal adenocarcinoma patients with short or long survival

“…It has been shown to facilitate various aspects of cancer, including sustained proliferation, angiogenesis, invasion, and metastasis. 40,41 A recent study by Law et al 42 used quantitative proteomics to analyze PDAC liver metastases and identified four distinct PDAC microenvironment subtypes, including an inflammatory subtype that did not respond to FOLFIRINOX treatment. This subtype was enriched for proteins related to complement activation and adaptive immune response, among others.…”

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts

“…These could be used to elucidate the molecular features and underlying pathogenesis of various tumors and contribute to the development of novel treatment strategies. For instance, proteomic profiling of diffuse-type gastric cancer and pancreatic ductal adenocarcinoma with liver metastases revealed their unique molecular signatures that helped develop an optimal treatment strategy ( 7 , 8 ). Similarly, proteomic analysis identified novel therapeutic targets of early-stage hepatocellular carcinoma ( 9 ).…”

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

“… 44 , 46 Importantly, patients with basal-like tumors have higher pathologic grades and worse OS compared with those with classical tumors. 44 , 46 , 48 , 50 , 330 Nevertheless, there is no consensus on subtype-specific treatment regimens. Although Collisson et al reported that QM-PDA subtype patients had significantly worse outcomes compared with patients with other subtypes, they found that in pancreatic cancer cells, the QM-PDA subtype was more sensitive to gemcitabine.…”

“… 48 Law et al reported proteomic-based subtyping of pancreatic cancer liver metastases and identified four distinct pancreatic cancer subtypes, i.e., metabolic, progenitor-like, proliferative, and inflammatory. 330 Pancreatic cancer patients with metabolic and progenitor-like subtypes showed significant benefit from FOLFIRINOX treatment.…”