Functional and Clinical Proteomic Exploration of Pancreatic Cancer

Abstract

Pancreatic cancer, in most cases being pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal cancers with a median survival time of less than 6 months. Therapeutic options are very limited for patients with PDAC, and surgery is still the most effective treatment, making improvements in early diagnosis critical. One typical characteristic of PDAC is the desmoplastic reaction of its stroma microenvironment, which actively interacts with cancer cells to orchestrate key components in tumorigenesis, metastasis, and chemoresistance. A global exploration of cancer-stroma crosstalk is essential to decipher PDAC biology and design intervention strategies. Over the past decade, the dramatic improvement in proteomics technologies has enabled the profiling of proteins, post-translational modifications (PTMs), and their protein complexes at unprecedented sensitivity and dimensionality. Here, starting with our current understanding of PDAC characteristics, including precursor lesions, progression models, tumor microenvironment, and therapeutic advancements, we describe how proteomics contributes to the functional and clinical exploration of PDAC, providing insights into PDAC carcinogenesis, progression, and chemoresistance. We summarize recent achievements enabled by proteomics to systematically investigate PTMs-mediated intracellular signaling in PDAC, cancer-stroma interactions, and potential therapeutic targets revealed by these functional studies. We also highlight proteomic profiling of clinical tissue and plasma samples to discover and verify useful biomarkers that can aid early detection and molecular classification of patients. In addition, we introduce spatial proteomic technology and its applications in PDAC for deconvolving tumor heterogeneity. Finally, we discuss future prospects of applying new proteomic technologies in comprehensively understanding PDAC heterogeneity and intercellular signaling networks. Importantly, we expect advances in clinical functional proteomics for exploring mechanisms of cancer biology directly by high-sensitivity functional proteomic approaches starting from clinical samples.

Keywords: cancer-stroma crosstalk; clinical proteomics; exosome; functional proteomics; pancreatic cancer; post-translational modifications; spatial proteomics; tumor microenvironment.

Graphical abstract

Fig. 1

Protein targets of clinical trials in the last 3 years that specifically investigated PDAC or included patients with PDAC. Proteins are classified according to their subcellular locations and molecular functions. The phases of clinical trials are indicated by the number of asterisk(s).

Fig. 2

Representative functional proteomic studies of PDAC.A, correlation analysis of global proteomic and phosphoproteomic datasets of 41 healthy tissues and 66 mouse Kras^G12D cell lines with their phenotypic data in response to radiation and drugs. B, IP-MS enabled identification of CA19-9 protein carriers, including FBLN3, modification of which by CA19-9 leads to EGFR hyperactivation and induction of pancreatitis and PDAC carcinogenesis. C, combination of metabolomics and proteomics revealed critical roles of transporters in alanine-mediated cancer-stroma crosstalk. D, generic and combinatory functional proteomics revealed LIF as a critical cytokine in stromal activation of cancer cell signaling, and targeted proteomics and digital ELISA validated LIF as a plasma biomarker for PDAC detection. Adapted with permission from References (31) (A), (34) (B), (41) (C), and (43) (D), respectively.

Fig. 3

Representative clinical proteomic studies of PDAC.A, Proteogenomic analysis of PDAC bulk tissues classified tumors into classical and basal-like subtypes, with the classical subtype showing a better prognosis than the basal-like subtype. B, LCM-based spatial proteomic and transcriptomic analyses of deserted and reactive subTMEs discovered by large-scale histological examination of PDAC slides. C, Proteomic analysis of cancer cell-derived exosomes identified PDAC exosome-specific proteins, which were validated as PDAC biomarkers with high specificity. Adapted with permission from References (35) (A), (66) (B), and (78, 79, 81) (C), respectively.