bims-mecami 2024-10-27 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–10–27
ten papers selected by
Oltea Sampetrean, Keio University

Metabolic Reprogramming of Cancer-Associated Fibroblast in the Tumor Microenvironment: From Basics to Clinic.
Transgelin 2 guards T cell lipid metabolism and antitumour function.
A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.
Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment.
Cell calcification reverses the chemoresistance of cancer cells via the conversion of glycolipid metabolism.
Computational dissection of the regulatory mechanisms of aberrant metabolism in remodeling the microenvironment of breast cancer.
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment.
Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors.
Optimizing CD8+ T cell-based immunotherapy via metabolic interventions: a comprehensive review of intrinsic and extrinsic modulators.
Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.

Clin Med Insights Oncol. 2024 ;18 11795549241287058

Metabolic Reprogramming of Cancer-Associated Fibroblast in the Tumor Microenvironment: From Basics to Clinic.

Lujia Zhou, Wenjie Zhang, Xiaoxue Hu, Daorong Wang, Dong Tang.

  Metabolic reprogramming occurs when tumor cells replenish themselves with nutrients required for growth to meet their metabolic needs. Cancer-associated fibroblasts (CAFs) are activated fibroblasts involved in building the c (TME) to promote tumor progression and metastasis. Metabolic reprogramming of CAFs can interact with cancer cells to generate metabolic crosstalk. Furthermore, CAF metabolic reprogramming has great potential as a new field of tumor treatment. This review summarizes the role of CAFs in TME and the mechanisms by which metabolic reprogramming of CAFs causes cancer progression and metastasis, demonstrating the great potential of CAF metabolic reprogramming in cancer chemotherapy and immunotherapy treatment. Furthermore, we provide an outlook for future CAF metabolic reprogramming for cancer treatment.

Keywords:  CAFs; Metabolic reprogramming; chemotherapy; immunotherapy; metastasis

DOI:  https://doi.org/10.1177/11795549241287058
Nature. 2024 Oct 23.

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito A Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matías Marin Falco, Camilla Salvagno, Alexander Emmanuelli, Ian T McBain, Bikash Mishra, Lionel B Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana K Morales, Xiaoqing Yu, Paulo C Rodriguez, Jose R Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song, Juan R Cubillos-Ruiz.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

DOI: https://doi.org/10.1038/s41586-024-08071-y
Int J Biol Sci. 2024 ;20(13): 5109-5126

A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.

Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi.

  Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.

Keywords:  Epithelial-mesenchymal transition; Metabolism; Tumor cells; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.99680
Cells. 2024 Oct 17. pii: 1721. [Epub ahead of print]13(20):

Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment.

Xingyu Chen, Zihan Wang, Bo Zhu, Min Deng, Jiayue Qiu, Yunwen Feng, Ning Ding, Chen Huang.

  Aging is an important risk factor for tumorigenesis. Metabolic reprogramming is a hallmark of both aging and tumor initiation. However, the manner in which the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to characterize aging-related metabolic plasticity events using pan-cancer bulk RNA-seq data. Our analysis revealed a high degree of metabolically organized heterogeneity across 17 aging-related cancer types. In particular, a higher degree of several energy generation pathways, i.e., glycolysis and impaired oxidative phosphorylation, was observed in older patients. Similar phenomena were also found via single-cell RNA-seq analysis. Furthermore, those energy generation pathways were found to be weakened in activated T cells and macrophages, whereas they increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter glucose utilization, thereby influencing immune function and resulting in the remodeling of the TME. This work offers new insights into the associations between tumor metabolism and the TME mediated by aging, linking with novel strategies for cancer therapy.

Keywords:  aging; glioma; metabolic plasticity; metabolic reprogramming; pan-cancer; scRNA sequencing analysis; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cells13201721
Biomaterials. 2024 Oct 10. pii: S0142-9612(24)00420-4. [Epub ahead of print]314 122886

Cell calcification reverses the chemoresistance of cancer cells via the conversion of glycolipid metabolism.

Lihong Zhang, Yandi Sun, Yindan Lin, Hanhui Li, Yuqiao Huang, Ning Tang, Xueyun Zhang, Yin Lu, Vassili A Kovalev, Eduard V Snezhko, Yan Luo, Ben Wang.

  Drug resistance is an inherent challenge during cancer chemotherapy. Cancer cells favor fatty acid metabolism through metabolic reprogramming to achieve therapeutic resistance. However, an effective approach to overcoming the switch from glycolysis-dependent to fatty acid beta-oxidation-dependent anabolic and energy metabolism remains elusive. Here, we developed a macromolecular drug (folate-polySia, FpSA) to induce the extracellular microcalcification of cervical cancer cells with cisplatin resistance. Microcalcification attenuated the uptake of fatty acids and the beta-oxidation of fatty acids by mitochondrial dysfunction but boosted the glycolysis pathway. Consequently, cotreatment with Pt and FpSA inhibited cisplatin-resistant tumor growth and improved tumor-bearing mice's survival rates, indicating that FpSA switched fatty acid metabolism to glycolysis to sensitize cisplatin-resistant cells further. Taken together, cancer cell calcification induced by FpSA provides a reprogramming metabolic strategy for the treatment of chemotherapy-resistant tumors.

Keywords:  Cancer calcification; Cervical cancer; Chemoresistant; Chemotherapy adjuvant; Glycolipid metabolism

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122886
Yi Chuan. 2024 Oct;46(10): 871-885

Computational dissection of the regulatory mechanisms of aberrant metabolism in remodeling the microenvironment of breast cancer.

Yu-Xin Wan, Xin-Yu Zhu, Yu Zhao, Na Sun, Tian-Tong-Fei Jiang, Juan Xu.

  The composition of T cell subsets and tumor-specific T cell interactions within the tumor microenvironment (TME) contribute to the heterogeneity observed in breast cancer. Moreover, aberrant tumor metabolism is often intimately linked to dysregulated anti-tumor immune function of T cells. Identifying key metabolic genes that affect immune cell interactions thus holds promise for uncovering potential therapeutic targets in the treatment of breast cancer. This study leverages single-cell transcriptomic data from breast cancer to investigate tumor-specific T-cell subsets and their interacting subnetworks in the TME during cancer progression. We further assess the metabolic pathway activities of tumor-specifically activated T-cell subsets. The results reveal that metabolic pathways involved in insulin synthesis, secretion, degradation, as well as fructose catabolism, significantly influence multiple T cell interactions. By integrating the metabolic pathways that significantly up-regulate T cells in tumors and influence their interactions, we identify key abnormal metabolic genes associated with T-cell collaboration and further develop a breast cancer risk assessment model. Additionally, using gene expression profiles of prognosis-related genes significantly associated with aberrant metabolism and drug IC50 values, we predict targeted drugs, yielding potential candidates like GSK-J4 and PX-12. This study integrate the analysis of abnormal T-cell interactions and metabolic pathway abnormalities in the breast cancer TME, elucidating their roles in cancer progression and providing leads for novel breast cancer therapeutic strategies.

Keywords:  T-cell interactions; aberrant metabolism; breast cancer; microenvironmental remodelling

DOI:  https://doi.org/10.16288/j.yczz.24-167
Nat Rev Cancer. 2024 Oct 24.

Convergent inducers and effectors of T cell paralysis in the tumour microenvironment.

Douglas Hanahan, Olivier Michielin, Mikael J Pittet.

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.

DOI: https://doi.org/10.1038/s41568-024-00761-z
Front Oncol. 2024 ;14 1428802

Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors.

Zafer Gurel, Michael S Luy, Qianyun Luo, Nicholas L Arp, Amy K Erbe, Aparna H Kesarwala, Jing Fan, Randall J Kimple.

   Introduction: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor.
Methods: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors.
Results: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs.
Conclusions: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma.

Keywords:  LDH; NHI-2; cancer metabolism; immune checkpoint inhibitors; lactate; melanoma; oxamate

DOI:  https://doi.org/10.3389/fonc.2024.1428802
Exp Hematol Oncol. 2024 Oct 22. 13(1): 103

Optimizing CD8+ T cell-based immunotherapy via metabolic interventions: a comprehensive review of intrinsic and extrinsic modulators.

Zihao Zhou, Jiarong Zheng, Ye Lu, Zizhao Mai, Yunfan Lin, Pei Lin, Yucheng Zheng, Xu Chen, Rongwei Xu, Xinyuan Zhao, Li Cui.

  CD8+ T cells are integral to the effective management of cancer and infectious diseases due to their cytotoxic functions. The efficacy of these cells is profoundly influenced by their metabolic state, which regulates their activation, differentiation, and longevity. Accordingly, the modulation of metabolic pathways within CD8+ T cells is crucial for enhancing the effectiveness of T cell-based immunotherapy. Precise metabolic control is paramount in optimizing therapeutic outcomes and minimizing potential toxicities associated with treatment. Importantly, the potential of exogenous metabolites to augment CD8+ T cell responses is critically evaluated, especially through in vivo evidence that underscores their therapeutic promise. This review also addresses current challenges, including the need for precise control of metabolic modulation to avoid adverse effects, the development of targeted delivery systems to ensure efficient metabolite delivery to CD8+ T cells, and the inherent variability of metabolic states among patients that may influence treatment outcomes. Addressing these hurdles will be crucial for the successful integration of metabolic interventions into established immunotherapeutic regimens.

Keywords:  CD8+ T cells; Exogenous metabolites; Metabolic modulation; T cell-based immunotherapy; Therapeutic optimization

DOI:  https://doi.org/10.1186/s40164-024-00575-7
Cell Metab. 2024 Oct 18. pii: S1550-4131(24)00395-4. [Epub ahead of print]

Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.

Chenxi Zhao, Tingting Zhang, Si-Tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li.

  Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.

Keywords:  ARF1; GSH; SCARB2; adipocyte; breast cancer; glutathione; lysosomal integral membrane protein-2; mTORC1; mammalian target of rapamycin complex 1; obesity

DOI:  https://doi.org/10.1016/j.cmet.2024.09.013