bims-mecami 2023-12-17 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–12–17
twelve papers selected by
Oltea Sampetrean, Keio University

The interplay of the circadian clock and metabolic tumorigenesis.
Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma.
Re-"Formate" T-cell Antitumor Responses.
Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer.
Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.
Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment.
Neuromedin U regulates the anti-tumor activity of CD8+ T cells and glycolysis of tumor cells in the tumor microenvironment of pancreatic ductal adenocarcinoma in an NMUR1-dependent manner.
Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival.
Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma.
PD-1H/VISTA mediates immune evasion in acute myeloid leukemia.
Lipid metabolism-related gene expression in the immune microenvironment predicts prognostic outcomes in renal cell carcinoma.

Trends Cell Biol. 2023 Dec 06. pii: S0962-8924(23)00237-4. [Epub ahead of print]

The interplay of the circadian clock and metabolic tumorigenesis.

Zheng Wang, Leina Ma, Ying Meng, Jing Fang, Daqian Xu, Zhimin Lu.

  The circadian clock and cell metabolism are both dysregulated in cancer cells through intrinsic cell-autonomous mechanisms and external influences from the tumor microenvironment. The intricate interplay between the circadian clock and cancer cell metabolism exerts control over various metabolic processes, including aerobic glycolysis, de novo nucleotide synthesis, glutamine and protein metabolism, lipid metabolism, mitochondrial metabolism, and redox homeostasis in cancer cells. Importantly, oncogenic signaling can confer a moonlighting function on core clock genes, effectively reshaping cellular metabolism to fuel cancer cell proliferation and drive tumor growth. These interwoven regulatory mechanisms constitute a distinctive feature of cancer cell metabolism.

Keywords:  cancer metabolism; dysregulated circadian clock; moonlighting function

DOI:  https://doi.org/10.1016/j.tcb.2023.11.004
Mol Ther Oncolytics. 2023 Dec 19. 31 100744

Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma.

Mohadeseh Hasanpourghadi, Arezki Chekaoui, Sophia Kurian, Raj Kurupati, Robert Ambrose, Wynetta Giles-Davis, Amara Saha, Xu Xiaowei, Hildegund C J Ertl.

  Adoptive transfer of tumor antigen-specific CD8+ T cells can limit tumor progression but is hampered by the T cells' rapid functional impairment within the tumor microenvironment (TME). This is in part caused by metabolic stress due to lack of oxygen and glucose. Here, we report that fenofibrate treatment of human ex vivo expanded tumor-infiltrating lymphocytes (TILs) improves their ability to limit melanoma progression in a patient-derived xenograft (PDX) mouse model. TILs treated with fenofibrate, a peroxisome proliferator receptor alpha (PPARα) agonist, switch from glycolysis to fatty acid oxidation (FAO) and increase the ability to slow the progression of autologous melanomas in mice with freshly transplanted human tumor fragments or injected with tumor cell lines established from the patients' melanomas and ex vivo expanded TILs.

Keywords:  PDX mouse model; PPARα agonist treatment; T cell metabolism; melanoma; tumor antigen-specific T cells

DOI:  https://doi.org/10.1016/j.omto.2023.100744
Cancer Discov. 2023 Dec 12. 13(12): 2507-2509

Re-"Formate" T-cell Antitumor Responses.

Mei-Chun Lin, Sofie Hedlund Moller, Ping-Chih Ho.

SUMMARY: Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti-PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic vulnerability in the tumor microenvironment and improve the efficacy of immune checkpoint blockade. See related article by Rowe et al., p. 2566 (8).

DOI: https://doi.org/10.1158/2159-8290.CD-23-1059
Front Endocrinol (Lausanne). 2023 ;14 1265525

Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer.

Jian Xiong, Yiyuan Fu, Jiezheng Huang, Yibin Wang, Xiaolong Jin, Xiaoyan Wan, Liu Huang, Zheng Huang.

  Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer.

Keywords:  immune microenvironment; metabolism; ovarian cancer; senescence; therapeutic strategies

DOI:  https://doi.org/10.3389/fendo.2023.1265525
Nat Commun. 2023 Dec 13. 14(1): 8075

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

Yu Muta, Juan F Linares, Anxo Martinez-Ordoñez, Angeles Duran, Tania Cid-Diaz, Hiroto Kinoshita, Xiao Zhang, Qixiu Han, Yuki Nakanishi, Naoko Nakanishi, Thekla Cordes, Gurpreet K Arora, Marc Ruiz-Martinez, Miguel Reina-Campos, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Christian M Metallo, Timothy F Osborne, Maria T Diaz-Meco, Jorge Moscat.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

DOI: https://doi.org/10.1038/s41467-023-43690-5
Nat Commun. 2023 Dec 13. 14(1): 8260

Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.

Thomas Hu, Mayar Allam, Shuangyi Cai, Walter Henderson, Brian Yueh, Aybuke Garipcan, Anton V Ievlev, Maryam Afkarian, Semir Beyaz, Ahmet F Coskun.

Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.

DOI: https://doi.org/10.1038/s41467-023-43917-5
Best Pract Res Clin Haematol. 2023 Dec;pii: S1521-6926(23)00075-0. [Epub ahead of print]36(4): 101514

Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment.

Rebecca Masel, Megan E Roche, Ubaldo Martinez-Outschoorn.

  The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-β to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8+ T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.

Keywords:  Bioimaging; Cancer metabolism; Hodgkin Lymphoma; Immune evasion; Paraneoplastic syndromes; Tumor macroenvironment; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.beha.2023.101514
Cancer Sci. 2023 Dec 10.

Neuromedin U regulates the anti-tumor activity of CD8+ T cells and glycolysis of tumor cells in the tumor microenvironment of pancreatic ductal adenocarcinoma in an NMUR1-dependent manner.

Rui Zheng, Si Wang, Jia Wang, Mengnan Zhou, Qi Shi, Beixing Liu.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, which is lethal in approximately 90% of cases despite advanced standard therapies. A typical feature of PDAC is the immunosuppressive tumor microenvironment with multiple immunosuppressive factors including neurotransmitters. Recently, neuromedin U (NMU), a highly conserved neuropeptide with many physiological functions, has attracted attention for its roles in tumorigenesis and metastasis in several types of cancers. However, whether NMU affects PDAC progression remains unclear. In this study, using an orthotopic mouse model of PDAC in combination with bioinformatics analysis, we found that NMU was upregulated in tumor tissues from the patients with PDAC and positively correlated with a poor prognosis of the disease. Interestingly, knockout of the Nmu gene in mice enhanced the anti-tumor functions of tumor-infiltrating CD8+ T cells in an NMU receptor 1-dependent manner. Additionally, NMU promoted the glycolytic metabolism of mouse PDAC tumors. The activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH), pivotal enzymes involved in the regulation of lactate production, were markedly reduced in tumor tissues from NMU-knockout mice. In vitro the presence of LDHA inhibitor can reduce the production of lactic acid stimulated by NMU, which can increase the anti-tumor activity of CD8+ T cells. Moreover, treatment of the pancreatic cancer cells with a phosphoinositide 3-kinase (PI3K) inhibitor diminished NMU-induced lactate production and the activities of PK and LDH, suggesting that NMU might regulate glycolysis via the PI3K/AKT pathway.

Keywords:  CD8+ T cells; glycolysis; neuromedin U; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.16024
bioRxiv. 2023 Dec 01. pii: 2023.11.30.569407. [Epub ahead of print]

Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival.

Constantine N Tzouanas, Marc S Sherman, Jessica E S Shay, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Evelyn Y Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Georg M Lauer, Ömer H Yilmaz, Wolfram Goessling, Alex K Shalek.

Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi-omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi-omic computational gene regulatory inference framework and human in vitro and mouse in vivo genetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.

DOI: https://doi.org/10.1101/2023.11.30.569407
Cancer Innov. 2022 Oct;1(3): 229-239

Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma.

Ting Zhu, Xiaoqin Ge, Shengping Gong, Shenchao Guo, Qingsong Tao, Jianxin Guo, Ruishuang Ma.

   Background: Hypoxic microenvironment is immunosuppressive and protumorigenic, and elevated lactate is an intermediary in the modulation of immune responses. However, as critical lactate transporters, the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.
Methods: Gene expression in low- and high-grade glioma (LGG and GBM) was evaluated with TCGA database. The TISIDB, TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints.
Results: Compared with normal tissues, a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM, and closely related to the poor prognosis only in LGG. Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflammation in glioma. The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis. TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells, which was correlated to tumor-associated macrophages and neutrophils that are immunosuppressive. SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints (especially PD1, PD-L1, PD-L2, Tim-3) and immunosuppressive factors (TGF-β and IL-10) in glioma. Furthermore, SLC16A3 had a positive correlation to activation markers of tumor-associated neutrophils and chemokines such as CCL2, CCL22, CXCR2, CXCR4 in LGG and CCL7, CCL20 CXCL8 in GBM, which could enhance infiltration of immunosuppressive cells to the tumor microenvironment.
Conclusion: In general, our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immunosuppressive cell infiltration, which contributes to immune evasion and a worse prognosis in glioma. Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.

Keywords:  SLC16A1 (MCT1); SLC16A3 (MCT4); glioma; immune checkpoints; immune evasion

DOI:  https://doi.org/10.1002/cai2.32
J Clin Invest. 2023 Dec 07. pii: e164325. [Epub ahead of print]

PD-1H/VISTA mediates immune evasion in acute myeloid leukemia.

Tae Kon Kim, Xue Han, Qianni Hu, Esten N Vandsemb, Carly M Fielder, Junshik Hong, Kwang Woon Kim, Emily F Mason, R Skipper Plowman, Jun Wang, Qi Wang, Jian-Ping Zhang, Ti Badri, Miguel F Sanmamed, Linghua Zheng, Tianxiang Zhang, Jude Alawa, Sang Won Lee, Amer M Zeidan, Stephanie Halene, Manoj M Pillai, Namrata S Chandhok, Jun Lu, Mina L Xu, Steven D Gore, Lieping Chen.

  Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics such as targeted therapy and immunotherapy, including anti-PD therapy. We demonstrate that Programmed Death-1 Homolog (PD-1H), an immune co-inhibitory molecule is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells have the expression of PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell surface PD-1H by antibody blockade or genetic targeting significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression as well and the combination of PD-1H blockade with PD-1 blockade conferred a synergistic anti-leukemia effect. Our findings provide the basis for PD-1H as an attractive therapeutic target to treat human AML.

Keywords:  Cancer immunotherapy; Costimulation; Immunology; Leukemias; Oncology

DOI:  https://doi.org/10.1172/JCI164325
Front Immunol. 2023 ;14 1324205

Lipid metabolism-related gene expression in the immune microenvironment predicts prognostic outcomes in renal cell carcinoma.

Qian Zhang, Bingbiao Lin, Huikun Chen, Yinyan Ye, Yijie Huang, Zhen Chen, Jun Li.

   Background: Rates of renal cell carcinoma (RCC) occurrence and mortality are steadily rising. In an effort to address this issue, the present bioinformatics study was developed with the goal of identifying major lipid metabolism biomarkers and immune infiltration characteristics associated with RCC cases.
Methods: The Cancer Genome Atlas (TCGA) and E-MTAB-1980 were used to obtain matched clinical and RNA expression data from patients diagnosed with RCC. A LASSO algorithm and multivariate Cox regression analyses were employed to design a prognostic risk model for these patients. The tumor immune microenvironment (TIME) in RCC patients was further interrogated through ESTIMATE, TIMER, and single-cell gene set enrichment analysis (ssGSEA) analyses. Gene Ontology (GO), KEGG, and GSEA enrichment approaches were further employed to gauge the mechanistic basis for the observed results. Differences in gene expression and associated functional changes were then validated through appropriate molecular biology assays.
Results: Through the approach detailed above, a risk model based on 8 genes associated with RCC patient overall survival and lipid metabolism was ultimately identified that was capable of aiding in the diagnosis of this cancer type. Poorer prognostic outcomes in the analyzed RCC patients were associated with higher immune scores, lower levels of tumor purity, greater immune cell infiltration, and higher relative immune status. In GO and KEGG enrichment analyses, genes that were differentially expressed between risk groups were primarily related to the immune response and substance metabolism. GSEA analyses additionally revealed that the most enriched factors in the high-risk group included the stable internal environment, peroxisomes, and fatty acid metabolism. Subsequent experimental validation in vitro and in vivo revealed that the most significantly differentially expressed gene identified herein, ALOX5, was capable of suppressing RCC tumor cell proliferation, invasivity, and migration.
Conclusion: In summary, a risk model was successfully established that was significantly related to RCC patient prognosis and TIME composition, offering a robust foundation for the development of novel targeted therapeutic agents and individualized treatment regimens. In both immunoassays and functional analyses, dysregulated lipid metabolism was associated with aberrant immunological activity and the reprogramming of fatty acid metabolic activity, contributing to poorer outcomes.

Keywords:  biomarker; immune infiltration; lipid metabolism; renal cell carcinoma; risk model

DOI:  https://doi.org/10.3389/fimmu.2023.1324205