Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response

Wang, Yu; Liang, Yongfeng; Xu, Haiyan; Zhang, Xiao; Mao, Tiebo; Cui, Jiujie; Yao, Jiyong; Wang, Yongchao; Jiao, Feng; Xiao, Xiuying; Hu, Jiong; Xia, Qing; Zhang, Xiaofei; Wang, Xujun; Sun, Yongwei; Fu, Deliang; Shen, Lei; Xu, Ximing; Xue, Jing; Wang, Liwei

doi:10.1038/s41421-021-00271-4

Cited by 151 publications

(144 citation statements)

References 64 publications

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“…It was found that pancreatic ductal adenocarcinoma patients with abundant MeCAFs had a higher risk of metastasis but had a significantly better response to immunotherapy. 136 These results indicate that abnormal glycolysis directly or indirectly affects tumor metastasis. CAFs up‐regulate carnitine palmitoyltransferase 1A (CPT1A) to cause reduction of fatty acid oxidation, leading to peritoneal metastasis of colorectal cancer.…”

Section: Components and Mechanisms Involved In Metastasismentioning

confidence: 85%

“…analyzed CAFs by single‐cell sequencing combined with RNA‐sequence and divided CAFs into four types. 136 One of the subtypes has high glycolytic activity and is termed MeCAFs. It was found that pancreatic ductal adenocarcinoma patients with abundant MeCAFs had a higher risk of metastasis but had a significantly better response to immunotherapy.…”

Section: Components and Mechanisms Involved In Metastasismentioning

confidence: 99%

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Tumor metastasis: Mechanistic insights and therapeutic interventions

Liu

Yang

et al. 2021

MedComm

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Cancer metastasis is responsible for the vast majority of cancer‐related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial‐mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.

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Section: Components and Mechanisms Involved In Metastasismentioning

confidence: 85%

Section: Components and Mechanisms Involved In Metastasismentioning

confidence: 99%

Tumor metastasis: Mechanistic insights and therapeutic interventions

Liu

Yang

et al. 2021

MedComm

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“…However, in this study, we accurately determined the metabolic transformations that occur in CAFs. Previously, molecular analyses have revealed changes in metabolic genes expressed in CAFs [34][35][36]. These results suggested that CAFs within tumors have an active glycolytic metabolism.…”

Section: Metabolic Transformation In Cafsmentioning

confidence: 90%

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

Miyazaki

Mori

Akagi

et al. 2022

Cancers

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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.

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“…However, in this study, we accurately determined the metabolic transformations that occur in CAFs. Previously, molecular analyses have revealed changes in metabolic genes expressed in CAFs [33][34][35]. These results suggested that CAFs within tumors have an active glycolytic metabolism.…”

Section: Metabolic Transformation In Cafsmentioning

confidence: 90%

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

Miyazaki¹,

Mori²,

Akagi³

et al. 2022

Preprint

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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. In addition, we identified CAF-specific metabolites that were expressed during this reprogramming and determined their presence in the pancreatic tumor tissues of mouse models. 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.

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Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response

Cited by 151 publications

References 64 publications

Tumor metastasis: Mechanistic insights and therapeutic interventions

Tumor metastasis: Mechanistic insights and therapeutic interventions

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

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

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