bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–03–19
fourteen papers selected by
Oltea Sampetrean, Keio University
  1. Metabolic Challenges in Anticancer CD8 T Cell Functions.
  2. Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines.
  3. Characterization of glycometabolism and tumor immune microenvironment for predicting clinical outcomes in gastric cancer.
  4. Cancer hallmarks intersect with neuroscience in the tumor microenvironment.
  5. Metabolic crosstalk between stromal and malignant cells in the bone marrow niche.
  6. Diversity of mitochondrial networks in lung cancer imaged.
  7. ANO1 reprograms cholesterol metabolism and the tumor microenvironment to promote cancer metastasis.
  8. Activated fibroblasts in cancer: Perspectives and challenges.
  9. Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.
  10. Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis.
  11. Antitumor Therapy Targeting the Tumor Microenvironment.
  12. Impact of microbiota on breast cancer hormone therapy.
  13. Alleviating the hypoxic tumor microenvironment with MnO2-coated CeO2 nanoplatform for magnetic resonance imaging guided radiotherapy.
  14. Macrophages at the interface of the co-evolving cancer ecosystem.
  1. Immune Netw. 2023 Feb;23(1): e9
    Metabolic Challenges in Anticancer CD8 T Cell Functions.
    Andrea M Amitrano, Minsoo Kim.
      Cancer immunotherapies continue to face numerous obstacles in the successful treatment of solid malignancies. While immunotherapy has emerged as an extremely effective treatment option for hematologic malignancies, it is largely ineffective against solid tumors due in part to metabolic challenges present in the tumor microenvironment (TME). Tumor-infiltrating CD8+ T cells face fierce competition with cancer cells for limited nutrients. The strong metabolic suppression in the TME often leads to impaired T-cell recruitment to the tumor site and hyporesponsive effector functions via T-cell exhaustion. Growing evidence suggests that mitochondria play a key role in CD8+ T-cell activation, migration, effector functions, and persistence in tumors. Therefore, targeting the mitochondrial metabolism of adoptively transferred T cells has the potential to greatly improve the effectiveness of cancer immunotherapies in treating solid malignancies.
    Keywords:  CD8 Positive T lymphocytes; Chimeric antigen receptor therapy; Metabolism; Mitochondria
    DOI:  https://doi.org/10.4110/in.2023.23.e9
  2. Cancer Res. 2023 Mar 13. pii: CAN-22-2316. [Epub ahead of print]
    Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines.
    Simon Schwoerer, Francesco V Cimino, Manon Ros, Kaloyan M Tsanov, Charles Ng, Scott W Lowe, Carlos Carmona-Fontaine, Craig B Thompson.
      Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. CAF heterogeneity is frequently observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a dense and hypoxic stroma that features myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) that are thought to have opposing roles in tumor progression. While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs displayed a hypoxic gene expression and biochemical profile and were enriched in hypoxic regions of PDAC tumors, while myCAFs were excluded from these regions. Hypoxia led fibroblasts to acquire an inflammatory gene expression signature and synergized with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, HIF-1α stabilization was sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid co-cultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF-1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2316
  3. iScience. 2023 Mar 17. 26(3): 106214
    Characterization of glycometabolism and tumor immune microenvironment for predicting clinical outcomes in gastric cancer.
    Jinyao Shi, Zhouqiao Wu, Xiaolong Wu, Longtao Huangfu, Ting Guo, Xiaojing Cheng, Jing Han, Ziyu Li, Xiaofang Xing, Jiafu Ji.
      Recent evidence demonstrates that the reprogramming of energy metabolism can interact with the tumor immune microenvironment, thereby participating in the progression of cancer. In this study, multi-omics data of 2471 gastric cancer samples were used to identify tumor glycometabolism and its correlation with tumor immune microenvironment. A series of bioinformatic approaches were performed to establish a scoring system to predict the survival and response of chemotherapy and immunotherapy. Three glycometabolic subtypes and two immune clustering subgroups of gastric cancer were determined. We further established a Gluco-Immune Scoring system to quantify the cancer glycometabolic status and immune infiltration of individual patients. Patients with low Gluco-Immune Score were sensitive to adjuvant chemotherapy, while patients with high Gluco-Immune Score may benefit from immunotherapy. Our results indicate that in gastric cancer, the assessment of tumor glucose metabolism and immune microenvironment has application value for the prediction of curative effects and the formulation of combined treatment strategies.
    Keywords:  Cancer systems biology; Gastroenterology; Oncology
    DOI:  https://doi.org/10.1016/j.isci.2023.106214
  4. Cancer Cell. 2023 Mar 13. pii: S1535-6108(23)00040-5. [Epub ahead of print]41(3): 573-580
    Cancer hallmarks intersect with neuroscience in the tumor microenvironment.
    Douglas Hanahan, Michelle Monje.
      The mechanisms underlying the multistep process of tumorigenesis can be distilled into a logical framework involving the acquisition of functional capabilities, the so-called hallmarks of cancer, which are collectively envisaged to be necessary for malignancy. These capabilities, embodied both in transformed cancer cells as well as in the heterotypic accessory cells that together constitute the tumor microenvironment (TME), are conveyed by certain abnormal characteristics of the cancerous phenotype. This perspective discusses the link between the nervous system and the induction of hallmark capabilities, revealing neurons and neuronal projections (axons) as hallmark-inducing constituents of the TME. We also discuss the autocrine and paracrine neuronal regulatory circuits aberrantly activated in cancer cells that may constitute a distinctive "enabling" characteristic contributing to the manifestation of hallmark functions and consequent cancer pathogenesis.
    DOI:  https://doi.org/10.1016/j.ccell.2023.02.012
  5. Bone Rep. 2023 Jun;18 101669
    Metabolic crosstalk between stromal and malignant cells in the bone marrow niche.
    Hernán A Tirado, Nithya Balasundaram, Lotfi Laaouimir, Ayşegül Erdem, Nick van Gastel.
      Bone marrow is the primary site of blood cell production in adults and serves as the source of osteoblasts and osteoclasts that maintain bone homeostasis. The medullary microenvironment is also involved in malignancy, providing a fertile soil for the growth of blood cancers or solid tumors metastasizing to bone. The cellular composition of the bone marrow is highly complex, consisting of hematopoietic stem and progenitor cells, maturing blood cells, skeletal stem cells, osteoblasts, mesenchymal stromal cells, adipocytes, endothelial cells, lymphatic endothelial cells, perivascular cells, and nerve cells. Intercellular communication at different levels is essential to ensure proper skeletal and hematopoietic tissue function, but it is altered when malignant cells colonize the bone marrow niche. While communication often involves soluble factors such as cytokines, chemokines, and growth factors, as well as their respective cell-surface receptors, cells can also communicate by exchanging metabolic information. In this review, we discuss the importance of metabolic crosstalk between different cells in the bone marrow microenvironment, particularly concerning the malignant setting.
    Keywords:  Bone marrow; Bone metastasis; Cell metabolism; Cellular communication; Leukemia; Stromal cells
    DOI:  https://doi.org/10.1016/j.bonr.2023.101669
  6. Nature. 2023 Mar 15.
    Diversity of mitochondrial networks in lung cancer imaged.
      
    Keywords:  Cancer; Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-023-00427-0
  7. Cancer Res. 2023 Mar 13. pii: CAN-22-3490. [Epub ahead of print]
    ANO1 reprograms cholesterol metabolism and the tumor microenvironment to promote cancer metastasis.
    Chun-Miao Deng, Guo-Geng Zhang, Qin-Wen Liu, Jiao-Jiao Xu, Zhi-Chao Liu, Jing Yang, Tao-Yang Xu, Zhi-Gang Li, Fan Zhang, Bin Li.
      Tumor metastasis is a complex process. A better understanding of the mechanistic underpinnings of the metastatic cascade could uncover approaches to better prevent and target metastases. Here, we integrated transcriptomic profiling in primary esophageal squamous cell carcinoma (ESCC) and matched lymph node metastatic tissues and genome-wide CRISPR/Cas9 functional screening to identify the key drivers of cancer metastasis. Anoctamin 1 (ANO1) expression was found to be elevated in primary tumors and further increased in metastatic tissues. High expression of ANO1 was associated with poor patient survival, and ANO1 overexpression promoted cancer invasion and metastasis. Mechanistically, ANO1 inactivated the LXR pathway and increased intracellular cholesterol accumulation by interacting with JUN to repress the transcription of cholesterol hydroxylase, CYP27A1. In a paracrine manner, interleukin 1β (IL-1β) secreted from ANO1-expressing ESCC cancer cells activated NFκB signaling in fibroblasts to stimulate production of the chemokine CCL1, which in turn enhanced invasion of ESCC cancer cells. Furthermore, molecular docking and in silico screening of 1,500,000 small molecules identified K786-4469 as a lead compound that targeted ANO1 and suppressed cancer metastasis in vitro and in vivo. Overall, these findings uncover a non-canonical function of ANO1 in regulating cholesterol metabolism and fibroblast function, revealing ANO1 as a potential prognostic biomarker and therapeutic target for metastatic ESCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3490
  8. Cancer Cell. 2023 Mar 13. pii: S1535-6108(23)00043-0. [Epub ahead of print]41(3): 434-449
    Activated fibroblasts in cancer: Perspectives and challenges.
    Giuseppina Caligiuri, David A Tuveson.
      Activated fibroblasts in tumors, or cancer-associated fibroblasts (CAFs), have become a popular research area over the past decade. As important players in many aspects of tumor biology, with functions ranging from collagen deposition to immunosuppression, CAFs have been the target of clinical and pre-clinical studies that have revealed their potential pro- and anti-tumorigenic dichotomy. In this review, we describe the important role of CAFs in the tumor microenvironment and the technological advances that made these discoveries possible, and we detail the models that are currently available for CAF investigation. Additionally, we present evidence to support the value of encompassing CAF investigation as a future therapeutic avenue alongside immune and cancer cells while highlighting the challenges that must be addressed for successful clinical translation of new findings.
    Keywords:  activated fibroblasts; cancer-associated fibroblasts; stroma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2023.02.015
  9. J Immunother Cancer. 2023 03;pii: e006522. [Epub ahead of print]11(3):
    Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.
    Konstantinos Lontos, Yiyang Wang, Supriya K Joshi, Andrew T Frisch, McLane J Watson, Alok Kumar, Ashley V Menk, Yupeng Wang, Rachel Cumberland, Jason Lohmueller, Esteban Carrizosa, Benjamin Boyerinas, Greg M Delgoffe.
       BACKGROUND: Cellular immunotherapies for cancer represent a means by which a patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral T cells to tumor targets, showing remarkable potency in blood cancers. However, due to several resistance mechanisms, CAR-T cell therapies remain ineffective in solid tumors. We and others have shown the tumor microenvironment harbors a distinct metabolic landscape that produces a barrier to immune cell function. Further, altered differentiation of T cells within tumors induces defects in mitochondrial biogenesis, resulting in severe cell-intrinsic metabolic deficiencies. While we and others have shown murine T cell receptor (TCR)-transgenic cells can be improved through enhanced mitochondrial biogenesis, we sought to determine whether human CAR-T cells could be enabled through a metabolic reprogramming approach.
    MATERIALS AND METHODS: Anti-EGFR CAR-T cells were infused in NSG mice which bore A549 tumors. The tumor infiltrating lymphocytes were analyzed for exhaustion and metabolic deficiencies. Lentiviruses carrying PPAR-gamma coactivator 1α (PGC-1α), PGC-1αS571A and NT-PGC-1α constructs were used to co-transduce T cells with anti-EGFR CAR lentiviruses. We performed metabolic analysis via flow cytometry and Seahorse analysis in vitro as well as RNA sequencing. Finally, we treated therapeutically A549-carrying NSG mice with either PGC-1α or NT-PGC-1α anti-EGFR CAR-T cells. We also analyzed the differences in the tumor-infiltrating CAR-T cells when PGC-1α is co-expressed.
    RESULTS: Here, in this study, we show that an inhibition resistant, engineered version of PGC-1α, can metabolically reprogram human CAR-T cells. Transcriptomic profiling of PGC-1α-transduced CAR-T cells showed this approach effectively induced mitochondrial biogenesis, but also upregulated programs associated with effector functions. Treatment of immunodeficient animals bearing human solid tumors with these cells resulted in substantially improved in vivo efficacy. In contrast, a truncated version of PGC-1α, NT-PGC-1α, did not improve the in vivo outcomes.
    CONCLUSIONS: Our data further support a role for metabolic reprogramming in immunomodulatory treatments and highlight the utility of genes like PGC-1α as attractive candidates to include in cargo along with chimeric receptors or TCRs for cell therapy of solid tumors.
    Keywords:  Cell Engineering; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Translational Medical Research
    DOI:  https://doi.org/10.1136/jitc-2022-006522
  10. Int J Biol Sci. 2023 ;19(4): 1284-1298
    Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis.
    Yang Lv, WenTao Tang, YuQiu Xu, WenJu Chang, ZhiYuan Zhang, Qi Lin, MeiLing Ji, QingYang Feng, GuoDong He, JianMin Xu.
      Aim: Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide and immune checkpoint blockade therapy only benefit a small set of CRC patients. Tumor ferroptosis of CRC reflected immune-activation in our previous findings. Understanding the mechanisms underlying how to bolster CD8+ T cells function through ferroptosis in CRC tumor microenvironment (TME) will greatly benefit cancer immunotherapy. Methods: Genes between ferroptosis and CD8+ T cell function in CRC were screened through Cox, WGCNA and differential expression analysis. Immunohistochemistry and Immunofluorescence analysis were performed. Co-immunoprecipitation were performed to determine protein-protein interaction, mRNA level was determined by qRT-PCR. RSL3 was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring Transmission Electron Microscope analysis, MDA, Fe2+level and cell viability. Results: We screened APOL3 as the significant modulator for ferroptosis-related CD8+ infiltration in CRC. Next, by in vitro and in vivo, we found that increased APOL3 expression was positively correlated with sensitivity to ferroptosis and antitumor ability of CD8+ T cells. Next, we demonstrated that APOL3 can binds LDHA and promote its ubiquitylation-related degradation. Then, based on in vivo analysis and tumor specimen, we discovered the APOL3-LDHA axis can facilitate the tumor ferroptosis and cytotoxic ability of CD8+ T cells through increased IFNγ and decreased lactic acid concentration. Conclusion: The present study demonstrated that APOL3 promotes ferroptosis and immunotherapy in colorectal cancer cells. The present work provides us with a novel target to overcome drug resistance to ferroptosis and immunotherapy.
    Keywords:  CD8+ T cell infiltration; colorectal cancer; ferroptosis; ubiquitin
    DOI:  https://doi.org/10.7150/ijbs.74985
  11. J Oncol. 2023 ;2023 6886135
    Antitumor Therapy Targeting the Tumor Microenvironment.
    Yuewen Gao, Zhengwu Pan, Hongqi Li, Fei Wang.
      The development and progression of tumors in human tissues extensively rely on its surrounding environment, that is, tumor microenvironment which includes a variety of cells, molecules, and blood vessels. These components are modified, organized, and integrated to support and facilitate the growth, invasion, and metabolism of tumor cells, suggesting them as potential therapeutic targets in anticancer treatment. An increasing number of pharmacological agents have been developed and clinically applied to target the oncogenic components in the tumor microenvironment, and in this review, we will summarize these pharmacological agents that directly or indirectly target the cellular or molecular components in the tumor microenvironment. However, difficulties and challenges still exist in this field, which will also be reported in this literature.
    DOI:  https://doi.org/10.1155/2023/6886135
  12. Cell Stress. 2023 Mar;7(3): 12-19
    Impact of microbiota on breast cancer hormone therapy.
    Safae Terrisse, Laurence Zitvogel, Guido Kroemer.
      Recent observations indicate that the pathogenesis and prognosis of hormone-receptor breast cancer is not only dictated by the properties of the malignant cells but also by immune and microbial parameters. Thus, the immunosurveillance system retards the development of hormone-positive breast cancer and contributes to the therapeutic efficacy of estrogen receptor antagonists and aromatase inhibitors. Moreover, the anticancer immune response is profoundly modulated by the local and intestinal microbiota, which influences cancer cell-intrinsic signaling pathways, affects the composition and function of the immune infiltrate present in the tumor microenvironment and modulates the metabolism of estrogens. Indeed, specific bacteria in the gut produce enzymes that affect the enterohepatic cycle of estrogen metabolites, convert estrogens into androgens or generate estrogen-like molecules. The knowledge of these circuitries is in its infancy, calling for further in-depth analyses.
    Keywords:  breast cancer; hormone therapy; immunity; microbiota
    DOI:  https://doi.org/10.15698/cst2023.03.277
  13. J Nanobiotechnology. 2023 Mar 15. 21(1): 90
    Alleviating the hypoxic tumor microenvironment with MnO2-coated CeO2 nanoplatform for magnetic resonance imaging guided radiotherapy.
    Fen Pi, Xuanru Deng, Qian Xue, Lan Zheng, Hongxing Liu, Fang Yang, Tianfeng Chen.
       BACKGROUND: Radiotherapy is a commonly used tool in clinical practice to treat solid tumors. However, due to the unique microenvironment inside the tumor, such as high levels of GSH, overexpressed H2O2 and hypoxia, these factors can seriously affect the effectiveness of radiotherapy.
    RESULTS: Therefore, to further improve the efficiency of radiotherapy, a core-shell nanocomposite CeO2-MnO2 is designed as a novel radiosensitizer that can modulate the tumor microenvironment (TME) and thus improve the efficacy of radiation therapy. CeO2-MnO2 can act as a radiosensitizer to enhance X-ray absorption at the tumor site while triggering the response behavior associated with the tumor microenvironment. According to in vivo and in vitro experiments, the nanoparticles aggravate the killing effect on tumor cells by generating large amounts of ROS and disrupting the redox balance. In this process, the outer layer of MnO2 reacts with GSH and H2O2 in the tumor microenvironment to generate ROS and release oxygen, thus alleviating the hypoxic condition in the tumor area. Meanwhile, the manganese ions produced by degradation can enhance T1-weighted magnetic resonance imaging (MRI). In addition, CeO2-MnO2, due to its high atomic number oxide CeO2, releases a large number of electrons under the effect of radiotherapy, which further reacts with intracellular molecules to produce reactive oxygen species and enhances the killing effect on tumor cells, thus having the effect of radiotherapy sensitization. In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystem with radiosensitizing function.
    CONCLUSION: In conclusion, the nanomaterial CeO2-MnO2, as a novel radiosensitizer, greatly improves the efficiency of cancer radiation therapy by improving the lack of oxygen in tumor and responding to the tumor microenvironment, providing an effective strategy for the construction of nanosystems with radiosensitizing function.
    Keywords:  Antitumor; Core–shell nanocomposite; Hypoxia; MR imaging; Radiosensitizer
    DOI:  https://doi.org/10.1186/s12951-023-01850-1
  14. Cell. 2023 Mar 14. pii: S0092-8674(23)00163-0. [Epub ahead of print]
    Macrophages at the interface of the co-evolving cancer ecosystem.
    Daan J Kloosterman, Leila Akkari.
      Macrophages are versatile and heterogeneous innate immune cells undertaking central functions in balancing immune responses and tissue repair to maintain homeostasis. This plasticity, once co-opted by malignant outgrowth, orchestrates manifold reciprocal interactions within the tumor microenvironment, fueling the evolution of the cancer ecosystem. Here, we review the multilayered sources of influence that jointly underpin and longitudinally shape tumor-associated macrophage (TAM) phenotypic states in solid neoplasms. We discuss how, in response to these signals, TAMs steer tumor evolution in the context of natural selection, biological dispersion, and treatment resistance. A number of research frontiers to be tackled are laid down in this review to therapeutically exploit the complex roles of TAMs in cancer. Building upon knowledge obtained from currently applied TAM-targeting strategies and using next generation technologies, we propose conceptual advances and novel therapeutic avenues to rewire TAM multifaceted regulation of the co-evolving cancer ecosystem.
    Keywords:  cancer evolution; immunity; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2023.02.020
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