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. 2023 Apr 7:21:2631-2639.
doi: 10.1016/j.csbj.2023.04.003. eCollection 2023.

Metabolic reprogramming of cancer-associated fibroblasts in pancreatic cancer contributes to the intratumor heterogeneity of PET-CT

Qingcai Meng  1   2   3   4 , Zengli Fang  1   2   3   4 , Xiaoqi Mao  1   2   3   4 , Rong Tang  1   2   3   4 , Chen Liang  1   2   3   4 , Jie Hua  1   2   3   4 , Wei Wang  1   2   3   4 , Si Shi  1   2   3   4 , Xianjun Yu  1   2   3   4 , Jin Xu  1   2   3   4
Affiliations

Metabolic reprogramming of cancer-associated fibroblasts in pancreatic cancer contributes to the intratumor heterogeneity of PET-CT

Qingcai Meng et al. Comput Struct Biotechnol J. .

Abstract

Intratumor heterogeneity of positron emission tomography-computed tomography (PET-CT) is reflected by variable 18F-fluorodeoxyglucose (FDG) uptake. Increasing evidence has shown that neoplastic and non-neoplastic components can affect the total 18F-FDG uptake in tumors. Cancer-associated fibroblasts (CAFs) is considered as the main non-neoplastic components in tumor microenvironment (TME) of pancreatic cancer. Our study aims to explore the impact of metabolic changes in CAFs on heterogeneity of PET-CT. A total of 126 patients with pancreatic cancer underwent PET-CT and endoscopic ultrasound elastography (EUS-EG) before treatment. High maximum standardized uptake value (SUVmax) from the PET-CT was positively correlated with the EUS-derived strain ratio (SR) and indicated poor prognosis of patients. In addition, single-cell RNA analysis showed that CAV1 affected glycolytic activity and correlated with glycolytic enzyme expression in fibroblasts in pancreatic cancer. We also observed the negative correlation between CAV1 and glycolytic enzyme expression in the tumor stroma by using immunohistochemistry (IHC) assay in the SUVmax-high and SUVmax-low groups of pancreatic cancer patients. Additionally, CAFs with high glycolytic activity contributed to pancreatic cancer cell migration, and blocking CAF glycolysis reversed this process, suggesting that glycolytic CAFs promote malignant biological behavior in pancreatic cancer. In summary, our research demonstrated that the metabolic reprogramming of CAFs affects total 18F-FDG uptake in tumors. Thus, an increase in glycolytic CAFs with decreased CAV1 expression promotes tumor progression, and high SUVmax may be a marker for therapy targeting the neoplastic stroma. Further studies should clarify the underlying mechanisms.

Keywords: Cancer-associated fibroblasts; Metabolic reprogramming; PET-CT; Pancreatic cancer.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

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Graphical abstract
Fig. 1
Fig. 1
The correlation between SUVmax and EUS-SR. A. Sample graph of PET-CT and EUS-SR. B. There was a positive correlation between SUVmax and SR. A scatter plot of the relationship between SUVmax and SR is shown (Spearman’s R= 0.298, p < 0.01).
Fig. 2
Fig. 2
Dot plot showing the distribution of common fibroblast markers (DCN, TAGLN, COL3A1, COL1A1, FAP and CAV1) in selected pancreatic cancer-infiltrating fibroblasts.
Fig. 3
Fig. 3
Single-cell RNA analysis of CAFs in pancreatic cancer. A. UMAP plot showing the subclusters of selected fibroblasts. B. UMAP plot showing the relative glycolytic activity of each cell. C. Expression of CAV1 in each subcluster of fibroblasts.
Fig. 4
Fig. 4
The expression of CAV1 was related to CAF glycolysis. A. Negative association between glycolytic enzyme and CAV1 expression in CAFs (* p < 0.05, *** p < 0.001). B. Negative correlation between CAV1 and glycolytic enzyme expression in the tumor stroma as determined by IHC.
Fig. 5
Fig. 5
Blocking CAF glycolysis affected pancreatic cancer progression. A-B. Analysis of the effect of CAF glycolysis on wound closure as determined by wound-healing assay (200 ×, ** p < 0.01). C-D. Analysis of the effect of CAF glycolysis on migration capacity as determined by in vitro transwell migration assays (scale bar 100 µm, ** p < 0.01). CAFs were cocultured with pancreatic cancer cells after treatment with the glycolytic inhibitor 2-DG for 24 h.
See this image and copyright information in PMC

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