Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. Furthermore, we analyzed the metabolites in pancreatic tumor tissues in a mice model. The metabolites extracted as candidates in the in vitro experiments were also detected in the in vivo experiments. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.

Polyamines: the pivotal amines in influencing the tumor microenvironment

“…Proline is synthesized preferentially from P5C, which comes from glutamine and ornithine. Metabolomic analysis of adipose-derived CAFs discovered that polyamines, most notably putrescine, are elevated in CAFs when compared to their mesenchymal stem cell progenitors [ 117 ].…”

Review of optical methods for noninvasive imaging of skin fibroblasts—From in vitro to ex vivo and in vivo visualization

“…It is also worth emphasizing the importance of visualizing virus-infected and cancerous fibroblasts, because studying changes in the morphology, behavior and gene expression of fibroblasts will provide a better understanding of how viruses and cancer cells interact with host cells and manipulate them for their own benefit [36][37][38]. This information is important for the development of new methods for the diagnosis and treatment of viral infections and cancer [39,40].…”

Decoding Metabolic Symbiosis between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts Using Cultured Tumor Microenvironment

“…One way in which CAFs contribute to cancer progression is by altering the metabolic properties of the TME [ 19 , 20 , 21 , 22 ]. CAFs can enhance the glycolytic activity of cancer cells by secreting lactate, which is used by cancer cells as a source of energy [ 23 , 24 ]. Additionally, CAFs can stimulate the uptake of glucose by cancer cells through the secretion of growth factors such as insulin-like growth factor 1 (IGF-1) and transforming growth factor beta (TGF-β) [ 19 , 25 , 26 ].…”

“…CAFs also strongly contribute to the formation of a dense fibrotic stroma in the TME. This stroma can limit the delivery of oxygen and nutrients to cancer cells, creating a hypoxic environment that can further enhance the metabolic adaptation of cancer cells to survive and proliferate [ 24 , 27 ].…”

“…In the context of cancer research, metabolomic analysis can provide valuable insights into the metabolic alterations that occur in cancer cells and their interactions with the TME [ 34 ]. We previously used Capillary Electrophoresis-Time Of Flight Mass Spectrometry (CE-TOFMS) to perform targeted and untargeted metabolomic analysis of the cells [ 24 ]. Targeted analysis involves the quantification of specific metabolites, while untargeted analysis aims to identify and quantify all metabolites present in a sample.…”