In our pursuit of the optimal stratification strategy, we have conducted a comprehensive follow-up study involving 1,171 pancreatic ductal adenocarcinoma (PDAC) patients who underwent pancreatectomy at Ruijin Hospital. This effort has resulted in the creation of an in-house cohort, referred to as RJ-cohort. Our analysis of this entire cohort has unveiled the significant impact of adjuvant treatment on overall survival (OS).

  To delve deeper into the molecular mechanisms underlying the differences in OS, we have randomly selected 191 patients (>15% of the entire cohort) for proteomic profiling, thus forming RJ-cohort 1. This subset was specifically designed to predict the prognosis and outcome of adjuvant chemotherapy. Through this initiative, we have identified clinically relevant functional modules, we have established a proteomics-level prognostic risk model for PDAC, and we have validated the model in an independent, in-house cohort, designated as RJ-cohort 2. More importantly, we have discovered two novel protein markers that are closely correlated with adjuvant chemotherapy sensitivity in PDAC patients, and have validated these findings in an independent, in-house cohort (known as RJ-cohort 3), as well as in two multicentric external cohorts, namely, FR-cohort and SH-cohort.

  PDAC stands out as one of the most aggressive tumors. Analysis of our entire in-house RJ-cohort has revealed adjuvant therapy as the most influential factor with significant correlations to OS. In pursuit of forecasting the prognosis and adjuvant therapy outcomes, we have conducted proteomic profiling on a randomly selected of 191 patients from the entire cohort, thereby creating RJ-cohort 1.

  Key findings can be summarised as follows:

• Differential proteins with PDAC development. Principal-component analyses of 4,787 analyzable proteins revealed a clear separation between tumors and TACs in RJ-cohort 1, with 1,213 proteins significantly up-regulated and 864 proteins down-regulated in tumors as compared to TACs. Oncogenic signaling pathways, complement and coagulation cascades, and ECM-receptor interactions were upregulated in tumor samples. Metabolic pathways, oxidative phosphorylation, and ribosome were downregulated in tumor samples.
• Functional modules with clinical relevance. We performed weighted correlation network analysis on proteomic data for tumor samples, identifying a total of 32 functional modules, each associated with distinct biological processes and molecular pathways. We next explored the clinical relevance of these modules, finding associations with the serum CA19-9 level, patient age, tumor size, nervous invasiveness, the number of total lymph nodes, AJCC stage, and overall survival. Based on proteins from these functional modules, we established a prognostic risk model for PDAC through LASSO-Cox regression analysis. This model stratified PDAC patients into two groups, LASSO score-high and score-low, with worse and poor prognosis, respectively. We cross-validated LASSO-Cox regression model using an external PDAC cohort from CPTAC, as well as an in-house cohort of 50 PDAC patients, called RJ-cohort 2.
• NDUFB8 and CEMIP2 as indicators for PDAC adjuvant chemotherapy responders. Recognising the significant survival benefits of adjuvant chemotherapy following PDAC resection, we conducted comprehensive analyses of clinical and proteomic data to identify proteomic biomarkers with interaction effects on the outcome of adjuvant chemotherapy. We built Cox proportional-hazards models, incorporating chemotherapy-by-biomarker interaction terms for OS, ultimately identifying NDUFB8 and CEMIP2 as top two biomarkers indicative of PDAC adjuvant chemotherapy sensitivity. Patients with lower NDUFB8 abundance or higher CEMIP2 levels exhibited sensitivity to adjuvant chemotherapy and favorable survival outcomes, suggesting that they should consider adjuvant chemotherapy, particularly S-1 that is known for better tolerability in Asian patients. These two biomarkers are involved in pathways linked to chemotherapy vulnerability, as confirmed by RNA-seq analysis of NDUFB8- and CEMIP2-silencing cells. We also provided experimental evidence supporting the clinical value of these two protein biomarkers: using high and low IHC staining of NDUFB8 and CEMIP2 in an independent in-house PDAC cohort (RJ-cohort 3), as well as functional assays in PDAC cell lines. Furthermore, our findings were substantiated through ad hoc IHC staining in two multicentric external cohorts, namely FR-cohort from France and SH-cohort from Shanghai, China.
• Feasibility of Proteomics-Guided Prognosis and Biomarker-Aided Adjuvant Chemotherapy. Our comprehensive cohort-scale integrative analysis showcases the potential for proteomics-guided prognosis and the utilization of biomarkers to guide adjuvant chemotherapy for PDAC. This study lays the foundation for precision medicine in the field, offering a roadmap for future research and clinical applications.

Association between age at diabetes onset or diabetes duration and subsequent risk of pancreatic cancer: Results from a longitudinal cohort and mendelian randomization study

Lancet Regional Health - Western Pacific 2022

Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment

Gut 2022

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1

Journal of Hematology & Oncology 2022

Post-pancreatectomy Acute Pancreatitis after Pancreaticoduodenectomy: A Distinct Clinical Entity

Annals of Surgery 2022

Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort

EBioMedicine 2021

Epigenetic silencing of LncRNA LINC00261 promotes c-myc-mediated aerobic glycolysis by regulating miR-222-3p/HIPK2/ERK axis and sequestering IGF2BP1

Oncogene 2021

Learning Curve From 450 Cases of Robot-Assisted Pancreaticoduocectomy in a High-Volume Pancreatic Center Optimization of Operative Procedure and a Retrospective Study

Annals of Surgery 2021

Short-term Outcomes After Robot-Assisted vs Open Pancreaticoduodenectomy After the Learning Curve

JAMA Surgery 2020

An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma

Proceedings of the National Academy of Sciences of the United States of America 2019

Silencing of long noncoding RNA LINC00958 prevents tumor initiation of pancreatic cancer by acting as a sponge of microRNA-330-5p to down-regulate PAX8

Cancer Letters 2019

Melittin-induced long non-coding RNA NONHSAT105177 inhibits proliferation and migration of pancreatic ductal adenocarcinoma

Cell Death & Disease 2018

Long noncoding RNA NORAD, a novel competing endogenous RNA, enhances the hypoxia-induced epithelial-mesenchymal transition to promote metastasis in pancreatic cancer

Molecular Cancer 2017