bims-mecami 2023-07-16 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–07–16
six papers selected by
Oltea Sampetrean, Keio University

Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.
Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?
Decoding Metabolic Symbiosis between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts Using Cultured Tumor Microenvironment.
Transcriptomic landscape of endothelial cells: Key tumor microenvironment components indicating variable clinical outcomes in pancreatic ductal adenocarcinoma.
Acidosis-induced regulation of adipocyte G0S2 promotes crosstalk between adipocytes and breast cancer cells as well as tumor progression.
High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment.

Front Immunol. 2023 ;14 1157291

Tumor-associated macrophages: new insights on their metabolic regulation and their influence in cancer immunotherapy.

Li Xiao, Qiao Wang, Hongling Peng.

  Tumor-associated macrophages (TAMs) are a dynamic and heterogeneous cell population of the tumor microenvironment (TME) that plays an essential role in tumor formation and progression. Cancer cells have a high metabolic demand for their rapid proliferation, survival, and progression. A comprehensive interpretation of pro-tumoral and antitumoral metabolic changes in TAMs is crucial for comprehending immune evasion mechanisms in cancer. The metabolic reprogramming of TAMs is a novel method for enhancing their antitumor effects. In this review, we provide an overview of the recent research on metabolic alterations of TAMs caused by TME, focusing primarily on glucose, amino acid, and fatty acid metabolism. In addition, this review discusses antitumor immunotherapies that influence the activity of TAMs by limiting their recruitment, triggering their depletion, and re-educate them, as well as metabolic profiles leading to an antitumoral phenotype. We highlighted the metabolic modulational roles of TAMs and their potential to enhance immunotherapy for cancer.

Keywords:  amino acid metabolism; fatty acid metabolism; glucose metabolism; immunotherapy; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2023.1157291
Cancers (Basel). 2023 Jul 03. pii: 3473. [Epub ahead of print]15(13):

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

Paolo Chetta, Renuka Sriram, Giorgia Zadra.

  Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty acid catabolism are consistently reported during prostate cancer development and progression in association with androgen-receptor signaling. Therefore, the term "lipogenic phenotype" is frequently used to describe the complex metabolic rewiring that occurs in prostate cancer. However, a new scenario has emerged in which lactate may play a major role. Alterations in oncogenes/tumor suppressors, androgen signaling, hypoxic conditions, and cells in the tumor microenvironment can promote aerobic glycolysis in prostate cancer cells and the release of lactate in the tumor microenvironment, favoring immune evasion and metastasis. As prostate cancer is composed of metabolically heterogenous cells, glycolytic prostate cancer cells or cancer-associated fibroblasts can also secrete lactate and create "symbiotic" interactions with oxidative prostate cancer cells via lactate shuttling to sustain disease progression. Here, we discuss the multifaceted role of lactate in prostate cancer progression, taking into account the influence of the systemic metabolic and gut microbiota. We call special attention to the clinical opportunities of imaging lactate accumulation for patient stratification and targeting lactate metabolism.

Keywords:  biomarkers; lactate; metabolic imaging; monocarboxylate transporters; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15133473
Int J Mol Sci. 2023 Jul 03. pii: 11015. [Epub ahead of print]24(13):

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

Yuma Nihashi, Xiaoyu Song, Masamichi Yamamoto, Daiki Setoyama, Yasuyuki S Kida.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis, largely due to its unique tumor microenvironment (TME) and dense fibrotic stroma. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor growth and metastasis, contributing to the metabolic adaptation of PDAC cells. However, the metabolic interactions between PDAC cells and CAFs are not well-understood. In this study, an in vitro co-culture model was used to investigate these metabolic interactions. Metabolomic analysis was performed under monoculture conditions of Capan-1 PDAC cells and CAF precursor cells, as well as co-culture conditions of PDAC cells and differentiated inflammatory CAF (iCAF). Co-cultured Capan-1 cells displayed significant metabolic changes, such as increased 2-oxoglutaric acid and lauric acid and decreased amino acids. The metabolic profiles of co-cultured Capan-1 and CAFs revealed differences in intracellular metabolites. Analysis of extracellular metabolites in the culture supernatant showed distinct differences between Capan-1 and CAF precursors, with the co-culture supernatant exhibiting the most significant changes. A comparison of the culture supernatants of Capan-1 and CAF precursors revealed different metabolic processes while co-culturing the two cell types demonstrated potential metabolic interactions. In conclusion, this study emphasizes the importance of metabolic interactions between cancer cells and CAFs in tumor progression and highlights the role of TME in metabolic reprogramming.

Keywords:  cancer-associated fibroblasts (CAFs); metabolic reprogramming; pancreatic ductal adenocarcinoma (PDAC)

DOI:  https://doi.org/10.3390/ijms241311015
Environ Toxicol. 2023 Jul 14.

Transcriptomic landscape of endothelial cells: Key tumor microenvironment components indicating variable clinical outcomes in pancreatic ductal adenocarcinoma.

Peng Xie, Si-Yuan Tan, Hai-Feng Li, Hao-Dong Tang, Jia-Hua Zhou.

  Endothelial cells (ECs) present in the tumor microenvironment (TME) exhibit significant diversity that may impact the efficacy of anti-tumor treatments. Thus, our study sought to elucidate the various clusters of ECs present in pancreatic ductal adenocarcinoma (PDAC) and explore their possible interactions and influence on clinical outcomes. We obtained single-cell transcriptome data from 24 PDAC tumors and 11 normal pancreases, minimizing any batch effects between samples. Next, we compared the relative abundance of various ECs clusters across distinct sample types. Pseudo-time analysis was employed to investigate the differentiation origin of ECs. A variety of bioinformatics methods were used to investigate potential communication between ECs and malignant cells, as well as assess metabolic changes, pathway alterations, and immune-related markers expression within distinct EC clusters. Lastly, we investigated the impact of particular ECs clusters on patient prognosis in bulk transcriptome data. Our study identified seven distinct clusters of ECs, denoted as CA4+ ECs, MMP2+ ECs, SPP1+ ECs, MT1F+ ECs, CCL5+ ECs, RGS5+ ECs, and TYROBP+ ECs. Pseudo-time analysis suggested that the loss of CA4+ ECs and MT1F+ ECs may promote malignant progression. Cell communication elucidated that MT1F+ ECs exhibited the strongest outgoing interaction strength, whereas RGS5+ ECs displayed the strongest incoming interaction strength. Furthermore, TYROBP+ ECs exhibited greater metabolic activity, and notably, CCL5+ ECs displayed increased expression of immune-related molecules. Lastly, across cohorts of bulk transcriptome levels, CA4+ ECs, MT1F+ ECs, and RGS5+ ECs consistently demonstrated prognostic indicative effects. PDAC patients exhibit the presence of seven distinct EC clusters, each demonstrating significant metabolic and immunological heterogeneity. Targeted therapeutic approaches directed toward CA4+ ECs and MT1F+ ECs may prove advantageous in addressing challenges associated with PDAC treatment. Additionally, variations in the relative abundance of CA4+ ECs, MT1F+ ECs, and RGS5+ ECs were indicated as predictive of patient prognosis.

Keywords:  endothelial cells; immune microenvironment; pancreatic ductal adenocarcinoma; prognosis; transcriptome

DOI:  https://doi.org/10.1002/tox.23881
Cancer Lett. 2023 Jul 11. pii: S0304-3835(23)00257-4. [Epub ahead of print] 216306

Acidosis-induced regulation of adipocyte G0S2 promotes crosstalk between adipocytes and breast cancer cells as well as tumor progression.

Julie Cremer, Laura Brohée, Laura Dupont, Camille Lefevre, Raphaël Peiffer, Alicia M Saarinen, Olivier Peulen, Laure Bindels, Jun Liu, Alain Colige, Christophe F Deroanne.

  Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.

Keywords:  Acidosis; Adipose triglyceride lipase (ATGL); G0/G1 switch gene 2 (G0S2); Lipolysis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2023.216306
J Transl Med. 2023 07 11. 21(1): 461

High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment.

Chenggang Gao, Jiaoshun Chen, Jianwei Bai, Haoxiang Zhang, Yanyi Tao, Shihong Wu, Hehe Li, Heshui Wu, Qiang Shen, Tao Yin.

   BACKGROUND: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment.
METHODS: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding Protein (RBP) Immunoprecipitation]-seq were used to confirm the potential regulating role of peptidyl-tRNA hydrolase 1 homolog (PTRH1) on the stability of the PD-L1 mRNA. Postoperative specimens were used to identify the expression of PD-L1 and PTRH1 in pancreatic cancer. Co-culturing T cells with pancreatic cancer cells to explore the immunosuppressive effect of pancreatic tumor cells.
RESULTS: Our results revealed that a high dose of glucose enhanced the stability of the PD-L1 mRNA in pancreatic tumor cells by downregulating PTRH1 through RAS signaling pathway activation following epidermal growth factor receptor (EGFR) stimulation. PTRH1 overexpression significantly suppressed PD-L1 expression in pancreatic cells and improved the proportion and cytotoxic function of CD8+ T cells in the pancreatic TME of diabetic mice.
CONCLUSIONS: PTRH1, an RBP, plays a key role in the regulation of PD-L1 by high glucose and is closely related to anti-tumor immunity in the pancreatic TME.

Keywords:  Diabetes; PD-L1; Pancreatic ductal adenocarcinoma; RNA binding protein; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-023-04302-4