bims-mecami 2023-05-21 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023‒05‒21
six papers selected by
Oltea Sampetrean, Keio University

Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.
Uridine-derived ribose fuels glucose-restricted pancreatic cancer.
Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer.
Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth.
Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem.

Cell Commun Signal. 2023 May 19. 21(1): 116

Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.

Chuwen Jiang, Zhengting Jiang, Gengyu Sha, Daorong Wang, Dong Tang.

  Metastasis, the spread of a tumor or cancer from the primary site of the body to a secondary site, is a multi-step process in cancer progression, accounting for various obstacles in cancer treatment and most cancer-related deaths. Metabolic reprogramming refers to adaptive metabolic changes that occur in cancer cells in the tumor microenvironment (TME) to enhance their survival ability and metastatic potential. Stromal cell metabolism also changes to stimulate tumor proliferation and metastasis. Metabolic adaptations of tumor and non-tumor cells exist not only in the TME but also in the pre-metastatic niche (PMN), a remote TME conducive for tumor metastasis. As a novel mediator in cell-to-cell communication, small extracellular vesicles (sEVs), which have a diameter of 30-150 nm, reprogram metabolism in stromal and cancer cells within the TME by transferring bioactive substances including proteins, mRNAs and miRNAs (microRNAs). sEVs can be delivered from the primary TME to PMN, affecting PMN formation in stroma rewriting, angiogenesis, immunological suppression and matrix cell metabolism by mediating metabolic reprogramming. Herein, we review the functions of sEVs in cancer cells and the TME, how sEVs facilitate PMN establishment to trigger metastasis via metabolic reprogramming, and the prospective applications of sEVs in tumor diagnosis and treatment. Video Abstract.

Keywords:  Metabolic reprogramming; Metastasis; PMN; Tumor microenvironment; sEVs

DOI:  https://doi.org/10.1186/s12964-023-01136-x
Nature. 2023 May 17.

Uridine-derived ribose fuels glucose-restricted pancreatic cancer.

Zeribe C Nwosu, Matthew H Ward, Peter Sajjakulnukit, Pawan Poudel, Chanthirika Ragulan, Steven Kasperek, Megan Radyk, Damien Sutton, Rosa E Menjivar, Anthony Andren, Juan J Apiz-Saab, Zachary Tolstyka, Kristee Brown, Ho-Joon Lee, Lindsey N Dzierozynski, Xi He, Hari Ps, Julia Ugras, Gift Nyamundanda, Li Zhang, Christopher J Halbrook, Eileen S Carpenter, Jiaqi Shi, Leah P Shriver, Gary J Patti, Alexander Muir, Marina Pasca di Magliano, Anguraj Sadanandam, Costas A Lyssiotis.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

DOI: https://doi.org/10.1038/s41586-023-06073-w
Cancer Res. 2023 May 17. pii: CAN-22-3042. [Epub ahead of print]

Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer.

Xiaowen Huang, Tiantian Sun, Jilin Wang, Xialu Hong, Huimin Chen, Tingting Yan, Chengbei Zhou, Danfeng Sun, Chen Yang, TaChung Yu, Wenyu Su, Wan Du, Hua Xiong.

Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating anti-tumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer (CRC). Herein, using single-cell RNA sequencing, we showed that metformin remodels the immune landscape of CRC. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the CRC tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in CRC cells and increased in CD8+ T cells. Untreated CRC cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T cell function. Metformin in turn reduced tryptophan uptake by CRC cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in CRC cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3042
Cell Metab. 2023 May 05. pii: S1550-4131(23)00171-7. [Epub ahead of print]

Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.

Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang.

  Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.

Keywords:  CD8(+) T cell activation; FH; ZAP70; anti-tumor immune response; fumarate; fumarate hydrolase; succination; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2023.04.017
Commun Biol. 2023 05 13. 6(1): 519

Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth.

Daria Neyroud, Orlando Laitano, Aneesha Dasgupta, Christopher Lopez, Rebecca E Schmitt, Jessica Z Schneider, David W Hammers, H Lee Sweeney, Glenn A Walter, Jason Doles, Sarah M Judge, Andrew R Judge.

Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigate the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induces progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grow slower, and show an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 is necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.

DOI: https://doi.org/10.1038/s42003-023-04902-2
Nat Commun. 2023 May 19. 14(1): 2876

Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem.

Michaela Schwaiger-Haber, Ethan Stancliffe, Dhanalakshmi S Anbukumar, Blake Sells, Jia Yi, Kevin Cho, Kayla Adkins-Travis, Milan G Chheda, Leah P Shriver, Gary J Patti.

Tumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix assisted laser desorption ionization reveals alterations in multiple anabolic pathways. De novo fatty acid synthesis flux is increased by approximately 3-fold in glioma relative to surrounding healthy tissue. Fatty acid elongation flux is elevated even higher at 8-fold relative to surrounding healthy tissue and highlights the importance of elongase activity in glioma.

DOI: https://doi.org/10.1038/s41467-023-38403-x