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Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.

ABSTRACT: Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer.

SUBMITTER: Olivares O

PROVIDER: S-EPMC5504351 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.

Olivares Orianne O Mayers Jared R JR Gouirand Victoire V Torrence Margaret E ME Gicquel Tristan T Borge Laurence L Lac Sophie S Roques Julie J Lavaut Marie-Noëlle MN Berthezène Patrice P Rubis Marion M Secq Veronique V Garcia Stéphane S Moutardier Vincent V Lombardo Dominique D Iovanna Juan Lucio JL Tomasini Richard R Guillaumond Fabienne F Vander Heiden Matthew G MG Vasseur Sophie S

Nature communications 20170707

Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrie ...[more]

PMID: 28685754

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ?10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGF?-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.

Project description:Importance:Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown. Objectives:To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity. Design, Setting, and Participants:This cohort study used data on 278?936 patients with PDAC with database-defined race from the National Cancer Database from January 1, 2004, to December 31, 2015. The median follow-up for censored patients was 24 months. The National Cancer Database, comprising academic and community facilities, includes about 70% of new cancer diagnoses in the United States. Race-stratified receipt of therapy was the primary variable of interest. Multivariable analyses included additional demographic and clinical parameters. Data analysis was initially completed on November 30, 2018, and revised data analysis was completed on June 27, 2019. Main Outcomes and Measures:Overall survival was the primary outcome, analyzed with Kaplan-Meier and multivariable Cox proportional hazards regression modeling. Results:The cohort included 278?936 patients (137?121 women and 141?815 men; mean [SD] age, 68.72 [11.57] years); after excluding patients from other racial categories, 243?820 of the 278?936 patients (87.4%) were white and 35?116 of the 278?936 patients (12.6%) were black. Unadjusted median overall survival was longer for white patients than for black patients (6.6 vs 6.0 months; P?<?.001). Black patients presented at younger ages than white patients (15?819 of 35?116 [45.0%] vs 83?846 of 243?820 [34.4%] younger than 65 years; P?<?.001) and with more advanced disease (20?853 of 31?600 [66.0%] vs 135?317 of 220?224 [61.4%] with stage III or IV disease; P?<?.001). Black patients received fewer surgical procedures than white patients for potentially resectable stage II disease (4226 of 8097 [52.2%] vs 39?214 of 65?124 [60.2%]; P?<?.001) and slightly less chemotherapy for advanced disease (2756 of 4067 [67.8%] vs 17?296 of 25?227 [68.6%] for stage III disease [P?=?.001]; 8208 of 16?104 [51.0%] vs 58?603 of 105?616 [55.5%] for stage IV disease [P?<?.001]). Decreased survival for black patients persisted in multivariable modeling controlled for sociodemographic parameters (hazard ratio, 1.04 [95% CI, 1.02-1.05]). Conversely, modeling that controlled specifically for clinical parameters such as disease stage and treatment revealed a modest survival advantage (hazard ratio, 0.94 [95% CI, 0.93-0.96]) among black patients. Resection was the factor most strongly associated with overall survival (hazard ratio, 0.39 [95% CI, 0.38-0.39]). Conclusions and Relevance:Black patients with PDAC present at younger ages and with more advanced disease than white patients, suggesting that differences in tumor biology may exist. Black patients receive less treatment stage for stage and fewer surgical procedures for resectable cancers than white patients; these findings may be only partly associated with socioeconomic differences. When disease stage and treatment were controlled for, black patients had no decrease in survival.

Dataset Information

Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.

Publications

Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.

Similar Datasets

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