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

With great interest, we read the article by Law and colleagues (1). They describe the proteomic landscape of liver metastases of a patient cohort suffering from pancreatic cancer. Unsupervised classification showed four molecular subtypes in liver metastases. These subtypes correlate to chemosensitivity and prognosis. One limitation of subtyping in pancreatic cancer is the lack of consensus of previous transcriptomic subtypes, unknown functional relevance, and the need for correlation with IHC and/or phenotypic histology (2). This has resulted in lack of implementation in clinical practice. The proteomic subtypes described in this study can hopefully assists in validation of subtype-specific proteins. However, some key points of the study should be further discussed.

Protein identification by mass spectrometry was performed and data were filtered for proteins identified in the whole cohort. This boosts qualitative data for comparisons, however reduces variability and thus might exclude important low abundant processes. Moreover, samples were gathered upon death, which induces a complicated variable: progression of disease and subsequently heterogeneity of treatment, resistance, and patient characteristics. Pancreatic cancer shows resilience against treatment regimens, a plasticity that is not taken into account within this cohort. Therapeutic pressure can induce clonal selection, therefore reduces clinical relevance of identified subtypes from this heterogenous treatment cohort (3). Proteomic subtyping of both treatment-naïve primary tumors and liver metastasis would overcome this issue.

In addition, tumor purity can influence proteome landscapes, as we have previously shown, diluting tumor-specific signals (4). Indeed, the authors identify high stromal content in the samples. Single-cell analysis or laser-capture microdissection could aid to disentangle tumor from stromal signals and assist to uncover subtype-specific pancreatic cancer proteins. Importantly, the authors identify a metabolic subtype, which annotates as an exocrine subtype. This type has been topic of much debate. Its identification in liver metastases support the hypothesis of existence of a more differentiated pancreatic cancer type, as contamination of pancreatic tissue is unlikely in liver sampling.

Finally, the authors identified several proteins modulated by gemcitabine and demonstrated a reduction in gemcitabine sensitivity upon serine hydroxymethyltransferase 1 (SHMT1) knockdown. SHMT proteins are the major source of 1‐carbon units needed for nucleotide synthesis. Moreover, SHMT upregulation in numerous tumors suggested their role as promising anticancer drug target (5). Functional experiments on nucleotide pools in correlation to SHMT are warranted to elucidate the mechanism of resistance.

To conclude, we congratulate the authors with their research which uncovers important novel cancer-specific proteins and proteomic subtypes in liver metastases of pancreatic cancer, and believe that further studies are warranted to determine the clinical relevance of pancreatic cancer proteomics.

See the Response, p. 4127