bims-mecami 2023-04-16 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023–04–16
twenty papers selected by
Oltea Sampetrean, Keio University

Metabolic challenges and interventions in CAR T cell therapy.
Spatial metabolic heterogeneity of oligodendrogliomas at single-cell resolution.
Pancreatic cancer: Advances and challenges.
Fueling the Tumor Microenvironment with Cancer-Associated Adipocytes.
Metabolism in type 2 immune responses.
Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors.
Metabolic dependencies and targets in ovarian cancer.
Crosstalk between oxidative phosphorylation and immune escape in cancer: a new concept of therapeutic targets selection.
Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.
Pancreatic cancer and fibrosis: Targeting metabolic reprogramming and crosstalk of cancer-associated fibroblasts in the tumor microenvironment.
Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma.
Cells of the tumor microenvironment speak the Wnt language.
The intratumoral microbiota: From microniches to single cells.
M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism.
Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.
Dynamics and specificities of T cells in cancer immunotherapy.
Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.
Pre-cancer: From diagnosis to intervention opportunities.
CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness.
Development of pathway-oriented screening to identify compounds to control 2-methylglyoxal metabolism in tumor cells.

Sci Immunol. 2023 Apr 14. 8(82): eabq3016

Metabolic challenges and interventions in CAR T cell therapy.

Jhan-Jie Peng, Limei Wang, Zhiyu Li, Cheng-Lung Ku, Ping-Chih Ho.

Chimeric antigen receptor (CAR) T cells have achieved true clinical success in treating hematological malignancy patients, laying the foundation of CAR T cells as a new pillar of cancer therapy. Although these promising effects have generated strong interest in expanding the treatment of CAR T cells to solid tumors, reproducible demonstration of clinical efficacy in the setting of solid tumors has remained challenging to date. Here, we review how metabolic stress and signaling in the tumor microenvironment, including intrinsic determinants of response to CAR T cell therapy and extrinsic obstacles, restrict the efficacy of CAR T cell therapy in cancer treatment. In addition, we discuss the use of novel approaches to target and rewire metabolic programming for CAR T cell manufacturing. Last, we summarize strategies that aim to improve the metabolic adaptability of CAR T cells to enhance their potency in mounting antitumor responses and survival within the tumor microenvironment.

DOI: https://doi.org/10.1126/sciimmunol.abq3016
Brain Tumor Pathol. 2023 Apr 11.

Spatial metabolic heterogeneity of oligodendrogliomas at single-cell resolution.

Sai Batchu, Michael Joseph Diaz, Giona Kleinberg, Brandon Lucke-Wold.

  Oligodendrogliomas are a type of rare and incurable gliomas whose metabolic profiles have yet to be fully examined. The present study examined the spatial differences in metabolic landscapes underlying oligodendrogliomas and should provide unique insights into the metabolic characteristics of these uncommon tumors. Single-cell RNA-sequencing expression profiles from 4044 oligodendroglioma cells derived from tumors resected from four locations frontal, temporal, parietal, and frontotemporoinsular) and in which 1p/19q co-deletion and IDH1 or IDH2 mutations were confirmed were computationally analyzed through a robust workflow to elucidate relative differences in metabolic pathway activities among the different locations. Dimensionality reduction using metabolic expression profiles exhibited clustering corresponding to each location subgroup. From the 80 metabolic pathways examined, over 70 pathways had significantly different activity scores between location subgroups. Further analysis of metabolic heterogeneity suggests that mitochondrial oxidative phosphorylation accounts for considerable metabolic variation within the same locations. Steroid and fatty acid metabolism pathways were also found to be major contributors to heterogeneity. Oligodendrogliomas display distinct spatial metabolic differences in addition to intra-location metabolic heterogeneity.

Keywords:  1p/19q; IDH1; IDH2; Oligodendroglioma metabolism; Spatial metabolic heterogeneity

DOI:  https://doi.org/10.1007/s10014-023-00455-8
Cell. 2023 Apr 13. pii: S0092-8674(23)00142-3. [Epub ahead of print]186(8): 1729-1754

Pancreatic cancer: Advances and challenges.

Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca di Magliano, Anirban Maitra.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.

DOI: https://doi.org/10.1016/j.cell.2023.02.014
Cancer Res. 2023 Apr 14. 83(8): 1170-1172

Fueling the Tumor Microenvironment with Cancer-Associated Adipocytes.

Caroline Bouche, Daniela F Quail.

Despite their abundance throughout the body, adipocytes are often ignored for their contributions within the tumor microenvironment (TME). However, their role in fueling cancer is becoming increasingly apparent as interest in the TME has seen remarkable advances in recent years. A seminal study by Dirat and colleagues highlighted the essential impact of the peritumoral adipose tissue in breast cancer progression and was among the first to demonstrate that tumor cells can reprogram adipocytes within their immediate niche to adopt unique characteristics. These "cancer-associated adipocytes" (CAA) were found to exchange cytokines and lipids with tumor cells, leading to their metabolic rewiring and acquisition of proinflammatory and invasive phenotypes. These important discoveries have represented a breakthrough in understanding the bidirectional metabolic dialog between adipocytes and tumor cells, and have contributed renewed perspectives on the functional contributions of adipocytes within the TME. Moreover, the effects of CAA may be further amplified in the setting of obesity as lipids dramatically accumulate, providing insights into the link between breast cancer and its more advanced clinical state in obese conditions. Thus, the different molecular actors involved in the dialog between tumor cells and CAA represent promising therapeutic targets that may have particular relevance in improving prognosis in obese patients with cancer. See related article by Dirat and colleagues, Cancer Res 2011;71:2455-65.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0505
Immunity. 2023 Apr 11. pii: S1074-7613(23)00127-9. [Epub ahead of print]56(4): 723-741

Metabolism in type 2 immune responses.

Agnieszka M Kabat, Erika L Pearce, Edward J Pearce.

The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.

DOI: https://doi.org/10.1016/j.immuni.2023.03.007
Cancers (Basel). 2023 Mar 29. pii: 2043. [Epub ahead of print]15(7):

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors.

Min Chen, Huanrong Lan, Shiya Yao, Ketao Jin, Yun Chen.

  The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach.

Keywords:  cancer therapy; dual inhibitor; metabolic intervention; metabolic reprogramming

DOI:  https://doi.org/10.3390/cancers15072043
Pharmacol Ther. 2023 Apr 12. pii: S0163-7258(23)00077-3. [Epub ahead of print] 108413

Metabolic dependencies and targets in ovarian cancer.

Yaqi Zhang, Yinu Wang, Guangyuan Zhao, Sandra Orsulic, Daniela Matei.

  Reprogramming of cellular metabolism is a hallmark of cancer. Cancer cells undergo metabolic adaptations to maintain tumorigenicity and survive under the attack of immune cells and chemotherapy in the tumor microenvironment. Metabolic alterations in ovarian cancer in part overlap with findings from other solid tumors and in part reflect unique traits. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, acquire resistance to chemotherapy, maintain cancer stem cell phenotype and escape the effects of anti-tumor immune defense. In this review, we comprehensively review the metabolic signatures of ovarian cancer and their impact on cancer initiation, progression, and resistance to treatment. We highlight novel therapeutic strategies targeting metabolic pathways under development.

Keywords:  Endoplasmic reticulum stress; Glutamine; Glycolysis; Lipids; Metabolism; Ovarian cancer; Oxidative phosphorylation; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.pharmthera.2023.108413
Cell Oncol (Dordr). 2023 Apr 11.

Crosstalk between oxidative phosphorylation and immune escape in cancer: a new concept of therapeutic targets selection.

Xutong Qiu, Yi Li, Zhuoyuan Zhang.

   BACKGROUND: Cancer is increasingly recognized as a metabolic disease, with evidence suggesting that oxidative phosphorylation (OXPHOS) plays a significant role in the progression of numerous cancer cells. OXPHOS not only provides sufficient energy for tumor tissue survival but also regulates conditions for tumor proliferation, invasion, and metastasis. Alterations in OXPHOS can also impair the immune function of immune cells in the tumor microenvironment, leading to immune evasion. Therefore, investigating the relationship between OXPHOS and immune escape is crucial in cancer-related research. This review aims to summarize the effects of transcriptional, mitochondrial genetic, metabolic regulation, and mitochondrial dynamics on OXPHOS in different cancers. Additionally, it highlights the role of OXPHOS in immune escape by affecting various immune cells. Finally, it concludes with an overview of recent advances in antitumor strategies targeting both immune and metabolic processes and proposes promising therapeutic targets by analyzing the limitations of current targeted drugs.
CONCLUSIONS: The metabolic shift towards OXPHOS contributes significantly to tumor proliferation, progression, metastasis, immune escape, and poor prognosis. A thorough investigation of concrete mechanisms of OXPHOS regulation in different types of tumors and the combination usage of OXPHOS-targeted drugs with existing immunotherapies could potentially uncover new therapeutic targets for future antitumor therapies.

Keywords:  Cancer therapy; Immunotherapy; Metabolism; OXPHOS

DOI:  https://doi.org/10.1007/s13402-023-00801-0
Cancer Immunol Res. 2023 Apr 14. OF1-OF16

Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.

Dominique C Hinshaw, Gloria A Benavides, Brandon J Metge, Courtney A Swain, Sarah C Kammerud, Heba A Alsheikh, Amr Elhamamsy, Dongquan Chen, Victor Darley-Usmar, Jeffrey C Rathmell, Robert S Welner, Rajeev S Samant, Lalita A Shevde.

The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0426
Front Immunol. 2023 ;14 1152312

Pancreatic cancer and fibrosis: Targeting metabolic reprogramming and crosstalk of cancer-associated fibroblasts in the tumor microenvironment.

Xin Li, Jianbo Zhou, Xue Wang, Chunxi Li, Zifan Ma, Qiaoling Wan, Fu Peng.

  Pancreatic cancer is one of the most dangerous types of cancer today, notable for its low survival rate and fibrosis. Deciphering the cellular composition and intercellular interactions in the tumor microenvironment (TME) is a necessary prerequisite to combat pancreatic cancer with precision. Cancer-associated fibroblasts (CAFs), as major producers of extracellular matrix (ECM), play a key role in tumor progression. CAFs display significant heterogeneity and perform different roles in tumor progression. Tumor cells turn CAFs into their slaves by inducing their metabolic dysregulation, exacerbating fibrosis to acquire drug resistance and immune evasion. This article reviews the impact of metabolic reprogramming, effect of obesity and cellular crosstalk of CAFs and tumor cells on fibrosis and describes relevant therapies targeting the metabolic reprogramming.

Keywords:  cancer-associated fibroblasts; crosstalk; fibrosis; heterogeneity; metabolic reprogramming; pancreatic cancer

DOI:  https://doi.org/10.3389/fimmu.2023.1152312
bioRxiv. 2023 Mar 27. pii: 2023.03.26.534192. [Epub ahead of print]

Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma.

Christina Jackson, Christopher Cherry, Sadhana Bom, Arbor G Dykema, Elizabeth Thompson, Ming Zheng, Zhicheng Ji, Wenpin Hou, Runzhe Li, Hao Zhang, John Choi, Fausto Rodriguez, Jon Weingart, Srinivasan Yegnasubramanian, Michael Lim, Chetan Bettegowda, Jonathan Powell, Jennifer Eliesseff, Hongkai Ji, Drew Pardoll.

The diversity of genetic programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC), unique to glioblastoma (GBM) and absent in grades II and III tumors: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. The E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stemlike tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells. Our large-scale single-cell analysis elucidated unique MDSC populations as key facilitators of GBM progression and mediators of tumor immunosuppression, suggesting that targeting these specific myeloid compartments, including their metabolic programs, may be a promising therapeutic intervention in this deadly cancer.
One-Sentence Summary: Aggressive glioblastoma harbors two unique myeloid populations capable of promoting stem-like properties of tumor cells and suppressing T cell function in the tumor microenvironment.

DOI: https://doi.org/10.1101/2023.03.26.534192
Trends Mol Med. 2023 Apr 10. pii: S1471-4914(23)00066-7. [Epub ahead of print]

Cells of the tumor microenvironment speak the Wnt language.

Vladimir L Katanaev, Alexey Baldin, Tatiana V Denisenko, Denis N Silachev, Anna E Ivanova, Gennadiy T Sukhikh, Lee Jia, Lev A Ashrafyan.

  Wnt signaling plays numerous functions in cancer, from primary transformation and tumor growth to metastasis. In addition to these cancer cell-intrinsic functions, Wnt signaling emerges to critically control cross-communication among cancer cells and the tumor microenvironment (TME). Here, we summarize the evidence that not only multiple cancer cell types, but also cells constituting the TME 'speak the Wnt language'. Fibroblasts, macrophages, endothelia, and lymphocytes all use the Wnt language to convey messages to and from cancer cells and among themselves; these messages are important for tumor progression and fate. Decoding this language will advance our understanding of tumor biology and unveil novel therapeutic avenues.

Keywords:  Wnt; drug discovery; fibroblasts; immune cells; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2023.03.006
Cell. 2023 Apr 13. pii: S0092-8674(23)00272-6. [Epub ahead of print]186(8): 1532-1534

The intratumoral microbiota: From microniches to single cells.

Susan Bullman.

Solid tumors are composed of a complex and dynamic collection of cell types. Here I discuss the important relationships between cancer cells and bacterial members of the intratumoral microbiota that may provide a fitness advantage within the tumor ecological niche.

DOI: https://doi.org/10.1016/j.cell.2023.03.012
Sci Adv. 2023 Apr 14. 9(15): eadf8522

M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism.

Isabel Weinhäuser, Diego A Pereira-Martins, Luciana Y Almeida, Jacobien R Hilberink, Douglas R A Silveira, Lynn Quek, Cesar Ortiz, Cleide L Araujo, Thiago M Bianco, Antonio Lucena-Araujo, Jose Mauricio Mota, Shanna M Hogeling, Dominique Sternadt, Nienke Visser, Arjan Diepstra, Emanuele Ammatuna, Gerwin Huls, Eduardo M Rego, Jan Jacob Schuringa.

It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra-bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed "trained" leukemic blasts display increased mitochondrial metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.

DOI: https://doi.org/10.1126/sciadv.adf8522
Sci Transl Med. 2023 Apr 12. 15(691): eadd1016

Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.

Stefan Naulaerts, Angeliki Datsi, Daniel M Borras, Asier Antoranz Martinez, Julie Messiaen, Isaure Vanmeerbeek, Jenny Sprooten, Raquel S Laureano, Jannes Govaerts, Dena Panovska, Marleen Derweduwe, Michael C Sabel, Marion Rapp, Weiming Ni, Sean Mackay, Yannick Van Herck, Lendert Gelens, Tom Venken, Sanket More, Oliver Bechter, Gabriele Bergers, Adrian Liston, Steven De Vleeschouwer, Benoit J Van Den Eynde, Diether Lambrechts, Michiel Verfaillie, Francesca Bosisio, Sabine Tejpar, Jannie Borst, Rüdiger V Sorg, Frederik De Smet, Abhishek D Garg.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8+ T cells remain disputed. Using multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8+ T cell states. CD8+ T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8+ TEX). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4+:CD8+ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8+ T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8+ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8+ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.

DOI: https://doi.org/10.1126/scitranslmed.add1016
Nat Rev Cancer. 2023 Apr 12.

Dynamics and specificities of T cells in cancer immunotherapy.

Giacomo Oliveira, Catherine J Wu.

Recent advances in cancer immunotherapy - ranging from immune-checkpoint blockade therapy to adoptive cellular therapy and vaccines - have revolutionized cancer treatment paradigms, yet the variability in clinical responses to these agents has motivated intense interest in understanding how the T cell landscape evolves with respect to response to immune intervention. Over the past decade, the advent of multidimensional single-cell technologies has provided the unprecedented ability to dissect the constellation of cell states of lymphocytes within a tumour microenvironment. In particular, the rapidly expanding capacity to definitively link intratumoural phenotypes with the antigen specificity of T cells provided by T cell receptors (TCRs) has now made it possible to focus on investigating the properties of T cells with tumour-specific reactivity. Moreover, the assessment of TCR clonality has enabled a molecular approach to track the trajectories, clonal dynamics and phenotypic changes of antitumour T cells over the course of immunotherapeutic intervention. Here, we review the current knowledge on the cellular states and antigen specificities of antitumour T cells and examine how fine characterization of T cell dynamics in patients has provided meaningful insights into the mechanisms underlying effective cancer immunotherapy. We highlight those T cell subsets associated with productive T cell responses and discuss how diverse immunotherapies might leverage the pre-existing tumour-reactive T cell pool or instruct de novo generation of antitumour specificities. Future studies aimed at elucidating the factors associated with the elicitation of productive antitumour T cell immunity are anticipated to instruct the design of more efficacious treatment strategies.

DOI: https://doi.org/10.1038/s41568-023-00560-y
J Clin Invest. 2023 Apr 13. pii: e165028. [Epub ahead of print]

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.

Liang Zheng, Zi-Ran Zhu, Tal Sneh, Weituo Zhang, Zao-Yu Wang, Guang-Yu Wu, Wei He, Hong-Gang Qi, Hang Wang, Xiao-Yu Wu, Jonatan Fernández-García, Ifat Abramovich, Yun-Ze Xu, Jin Zhang, Eyal Gottlieb.

  Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection, there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified two tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as outstanding plasma biomarkers for early diagnosis (receiver operating characteristic area under curve (ROCAUC) = 0.98). These two molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Keywords:  Cancer; Genetic diseases; Metabolism; Molecular diagnosis; Oncology

DOI:  https://doi.org/10.1172/JCI165028
Cancer Cell. 2023 Apr 10. pii: S1535-6108(23)00085-5. [Epub ahead of print]41(4): 637-640

Pre-cancer: From diagnosis to intervention opportunities.

E Shelley Hwang, James Reading, Jun Yu, Gian Paolo Dotto, William M Grady, Bogdan Czerniak, Manuel Serrano.

The multi-step process of carcinogenesis implies the existence of pre-malignant yet altered states that involve both the potentially carcinogenic cell as well as its surrounding microenvironment. Experts discuss some tumor types for which clear pre-cancerous stages have been identified and mention key biological alterations used for diagnosis and intervention strategies.

DOI: https://doi.org/10.1016/j.ccell.2023.03.012
Immunity. 2023 Mar 29. pii: S1074-7613(23)00130-9. [Epub ahead of print]

CD8+ T cells promote HIV latency by remodeling CD4+ T cell metabolism to enhance their survival, quiescence, and stemness.

Simona Mutascio, Talia Mota, Lavinia Franchitti, Ashish A Sharma, Abigail Willemse, Sydney N Bergstresser, Hong Wang, Maura Statzu, Gregory K Tharp, Jared Weiler, Rafick-Pierre Sékaly, Steven E Bosinger, Mirko Paiardini, Guido Silvestri, R Brad Jones, Deanna A Kulpa.

  HIV infection persists during antiretroviral therapy (ART) due to a reservoir of latently infected cells that harbor replication-competent virus and evade immunity. Previous ex vivo studies suggested that CD8+ T cells from people with HIV may suppress HIV expression via non-cytolytic mechanisms, but the mechanisms responsible for this effect remain unclear. Here, we used a primary cell-based in vitro latency model and demonstrated that co-culture of autologous activated CD8+ T cells with HIV-infected memory CD4+ T cells promoted specific changes in metabolic and/or signaling pathways resulting in increased CD4+ T cell survival, quiescence, and stemness. Collectively, these pathways negatively regulated HIV expression and ultimately promoted the establishment of latency. As shown previously, we observed that macrophages, but not B cells, promoted latency in CD4+ T cells. The identification of CD8-specific mechanisms of pro-latency activity may favor the development of approaches to eliminate the viral reservoir in people with HIV.

Keywords:  CD8 T cells; CD8 suppression; HIV; HIV cure; HIV latency; HIV reservoir; T cell biology

DOI:  https://doi.org/10.1016/j.immuni.2023.03.010
Commun Chem. 2023 Apr 13. 6(1): 68

Development of pathway-oriented screening to identify compounds to control 2-methylglyoxal metabolism in tumor cells.

Kouichi Yanagi, Toru Komatsu, Yuuta Fujikawa, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Tasuku Ueno, Kenjiro Hanaoka, Yasuteru Urano.

Controlling tumor-specific alterations in metabolic pathways is a useful strategy for treating tumors. The glyoxalase pathway, which metabolizes the toxic electrophile 2-methylglyoxal (MG), is thought to contribute to tumor pathology. We developed a live cell-based high-throughput screening system that monitors the metabolism of MG to generate D-lactate by glyoxalase I and II (GLO1 and GLO2). It utilizes an extracellular coupled assay that uses D-lactate to generate NAD(P)H, which is detected by a selective fluorogenic probe designed to respond exclusively to extracellular NAD(P)H. This metabolic pathway-oriented screening is able to identify compounds that control MG metabolism in live cells, and we have discovered compounds that can directly or indirectly inhibit glyoxalase activities in small cell lung carcinoma cells.

DOI: https://doi.org/10.1038/s42004-023-00864-y