bims-tumime 2023-08-20 papers

bims-tumime

Biomed News

on Tumor microenvironment and metabolism

Issue of 2023–08–20
thirteen papers selected by
Alex Muir, University of Chicago

Parkin deficiency suppresses antigen presentation to promote tumor immune evasion and immunotherapy resistance.
Chemokines and receptors in the development and progression of malignant tumors.
Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways.
Profiling single cancer cell metabolism via high-content SRS imaging with chemical sparsity.
Glial cell-derived soluble factors increase the metastatic potential of pancreatic adenocarcinoma cells and induce epithelial-to-mesenchymal transition.
Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux.
The role of metabolism in cellular quiescence.
Iron promotes glycolysis to drive colon tumorigenesis.
Cancer-on-chip: a 3D model for the study of the tumor microenvironment.
Tumor microenvironment-derived monoacylglycerol lipase provokes tumor-specific immune responses and lipid profiles.
Sublethal engagement of apoptotic pathways in residual cancer.
Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression.
TNBC-derived Gal3BP/Gal3 complex induces immunosuppression through CD45 receptor.

Cancer Res. 2023 Aug 14. pii: CAN-22-2499. [Epub ahead of print]

Parkin deficiency suppresses antigen presentation to promote tumor immune evasion and immunotherapy resistance.

Renzo Perales-Linares, Nektaria Maria Leli, Hesham Mohei, Silvia Beghi, Osvaldo D Rivera, Nektarios Kostopoulos, Andrea Giglio, Subin S George, Mireia Uribe-Herranz, Francesca Costabile, Stefano Pierini, Sergei Pustylnikov, Giorgos Skoufos, Yoseph Barash, Artemis G Hatzigeorgiou, Constantinos Koumenis, Amit Maity, Michael T Lotze, Andrea Facciabene.

Parkin is an E3 ubiquitin ligase that plays a key role in the development of Parkinson's disease. Parkin defects also occur in numerous cancers, and a growing body of evidence indicates that Parkin functions as a tumor suppressor that impedes a number of cellular processes involved in tumorigenesis. Here, we generated murine and human models that closely mimic the advanced-stage tumors where Parkin deficiencies are found to provide deeper insights into the tumor suppressive functions of Parkin. Loss of Parkin expression led to aggressive tumor growth that was associated with poor tumor antigen presentation and limited antitumor CD8+ T cell infiltration and activation. The effect of Parkin deficiency on tumor growth was lost following depletion of CD8+ T cells. In line with previous findings, Parkin deficiency was linked with mitochondria-associated metabolic stress, PTEN degradation, and enhanced AKT activation. Increased AKT signaling led to dysregulation of antigen presentation, and treatment with the AKT inhibitor MK2206-HCl restored antigen presentation in Parkin-deficient tumors. Analysis of data from clear cell renal cell carcinoma patients indicated that Parkin expression was downregulated in tumors and that low expression correlated with reduced overall survival. Furthermore, low Parkin expression correlated with reduced patient response to immunotherapy. Overall, these results identify a role for Parkin deficiency in promoting tumor immune evasion that may explain the poor prognosis associated with loss of Parkin across multiple types of cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2499
Cytokine. 2023 Aug 15. pii: S1043-4666(23)00213-2. [Epub ahead of print]170 156335

Chemokines and receptors in the development and progression of malignant tumors.

Han-Qing Zhao, Jun Jiang.

  Cancer cells, endothelial cells, inflammatory cells and various cytokines form a part of the tumor microenvironment (TME). Chemokines constitute the largest family of cytokines, and are mainly secreted by tumor cells and inflammatory cells in the TME. They play an important role in tumor development and progression by promoting tumor growth and metastasis, angiogenesis, and targeting the chemoattraction of inflammatory cells. Currently, some chemokine receptor antagonists are being used in clinical trials as targeted anti-tumor drugs. In this article, we review the roles of chemokines in the development and progression of malignant tumors based on recently published papers, taking into consideration of the new anti-tumor therapeutic strategies targeting chemokines and receptors.

Keywords:  Chemokines; Immunotherapy; Malignant Tumors; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.cyto.2023.156335
Cancer Discov. 2023 Aug 16. pii: CD-23-0131. [Epub ahead of print]

Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways.

Sriram Venneti, Abed Rahman Kawakibi, Sunjong Ji, Sebastian M Waszak, Stefan R Sweha, Mateus Mota, Matthew Pun, Akash Deogharkar, Chan Chung, Rohinton S Tarapore, Samuel Ramage, Andrew Chi, Patrick Y Wen, Isabel Arrillaga-Romany, Tracy T Batchelor, Nicholas A Butowski, Ashley Sumrall, Nicole Shonka, Rebecca A Harrison, John de Groot, Minesh Mehta, Matthew D Hall, Doured Daghistani, Timothy F Cloughesy, Benjamin M Ellingson, Kevin Beccaria, Pascale Varlet, Michelle M Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Rajan Jain, Maureen Kachman, Heidi Baum, Charles F Burant, Sophie L Mottl, Rodrigo T Cartaxo, Vishal John, Dana Messinger, Tingting Qin, Erik Peterson, Peter Sajjakulnukit, Karthik Ravi, Alyssa Waugh, Dustin Walling, Yujie Ding, Ziyun Xia, Anna Schwendeman, Debra Hawes, Fusheng Yang, Alexander R Judkins, Daniel Wahl, Costas A Lyssiotis, Daniel de la Nava, Marta M Alonso, Augustine Eze, Jasper Spitzer, Susanne V Schmidt, Ryan J Duchatel, Matthew D Dun, Jason E Cain, Li Jiang, Sylwia A Stopka, Gerard Baquer, Michael S Regan, Mariella G Filbin, Nathalie Y R Agar, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Viveka N Yadav, Jacques Grill, Cassie Kline, Sabine Mueller, Adam Resnick, Javad Nazarian, Joshua E Allen, Yazmin Odia, Sharon L Gardner, Carl Koschmann.

H3K27M-mutant diffuse midline glioma (DMG) patients have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/CSF correlate samples from patients treated in two completed multi-site clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, while those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuro-glial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0131
Sci Adv. 2023 Aug 18. 9(33): eadg6061

Profiling single cancer cell metabolism via high-content SRS imaging with chemical sparsity.

Yuying Tan, Haonan Lin, Ji-Xin Cheng.

Metabolic reprogramming in a subpopulation of cancer cells is a hallmark of tumor chemoresistance. However, single-cell metabolic profiling is difficult because of the lack of a method that can simultaneously detect multiple metabolites at the single-cell level. In this study, through hyperspectral stimulated Raman scattering (hSRS) imaging in the carbon-hydrogen (C-H) window and sparsity-driven hyperspectral image decomposition, we demonstrate a high-content hSRS (h2SRS) imaging approach that enables the simultaneous mapping of five major biomolecules, including proteins, carbohydrates, fatty acids, cholesterol, and nucleic acids at the single-cell level. h2SRS imaging of brain and pancreatic cancer cells under chemotherapy revealed acute and adapted chemotherapy-induced metabolic reprogramming and the unique metabolic features of chemoresistance. Our approach is expected to facilitate the discovery of therapeutic targets to combat chemoresistance. This study illustrates a high-content, label-free chemical imaging approach that measures metabolic profiles at the single-cell level and warrants further research on cellular metabolism.

DOI: https://doi.org/10.1126/sciadv.adg6061
J Cancer Res Clin Oncol. 2023 Aug 12.

Glial cell-derived soluble factors increase the metastatic potential of pancreatic adenocarcinoma cells and induce epithelial-to-mesenchymal transition.

Balbina García-Reyes, Ivan Kuzmanov, Reiner Schneider, Bianca Schneiker, Patrik Efferz, Jörg C Kalff, Sven Wehner.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, characterized by the spreading of highly metastatic cancer cells, including invasion into surrounding nerves and perineural spaces. Nerves, in turn, can invade the tumor tissue and, through the secretion of neurotrophic factors, chemokines, and cytokines, contribute to PDAC progression. However, the contribution of the nerve-associated glial cells to PDAC progression is not well characterized.
METHODS: Two murine PDAC cell lines were cultured with the conditioned media (CM) of primary enteric glial cells or IMS32 Schwann cells (SCs). Different properties of PDAC cells, such as invasiveness, migratory capacity, and resistance to gemcitabine, were measured by RT-qPCR, microscopy, and MTT assays. Using a neuronal cell line, the observed effects were confirmed to be specific to the glial lineage.
RESULTS: Compared to the control medium, PDAC cells in the glial cell-conditioned medium showed increased invasiveness and migratory capacity. These cells showed reduced E-cadherin and increased N-cadherin and Vimentin levels, all markers of epithelial-mesenchymal transition (EMT). Primary enteric glial cell CM inhibited the proliferation of PDAC cells but preserved their viability, upregulated transcription factor Snail, and increased their resistance to gemcitabine. The conditioned medium generated from the IMS32 SCs produced comparable results.
CONCLUSION: Our data suggest that glial cells can increase the metastatic potential of PDAC cells by increasing their migratory capacity and inducing epithelial-to-mesenchymal transition, a re-programming that many solid tumors use to undergo metastasis. Glial cell-conditioned medium also increased the chemoresistance of PDAC cells. These findings may have implications for future therapeutic strategies, such as targeting glial cell-derived factor signaling in PDAC.

Keywords:  Cell culture models; Glial cells; PDAC; Pancreatic cancer; Schwann cells

DOI:  https://doi.org/10.1007/s00432-023-05133-y
Nat Commun. 2023 Aug 12. 14(1): 4883

Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux.

Yuefan Huang, Vakul Mohanty, Merve Dede, Kyle Tsai, May Daher, Li Li, Katayoun Rezvani, Ken Chen.

Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) to infer metabolic fluxes from bulk or single-cell transcriptomic data. Large-scale experiments using cell-lines, the cancer genome atlas (TCGA), and scRNA-seq data obtained from diverse cancer and immunotherapeutic contexts, including CAR-NK cell therapy, have validated METAFlux's capability to characterize metabolic heterogeneity and metabolic interaction amongst cell types.

DOI: https://doi.org/10.1038/s41467-023-40457-w
J Cell Sci. 2023 Aug 15. pii: jcs260787. [Epub ahead of print]136(16):

The role of metabolism in cellular quiescence.

Yipeng Du, Parul Gupta, Shenlu Qin, Matthew Sieber.

  Cellular quiescence is a dormant, non-dividing cell state characterized by significant shifts in physiology and metabolism. Quiescence plays essential roles in a wide variety of biological processes, ranging from microbial sporulation to human reproduction and wound repair. Moreover, when the regulation of quiescence is disrupted, it can drive cancer growth and compromise tissue regeneration after injury. In this Review, we examine the dynamic changes in metabolism that drive and support dormant and transiently quiescent cells, including spores, oocytes and adult stem cells. We begin by defining quiescent cells and discussing their roles in key biological processes. We then examine metabolic factors that influence cellular quiescence in both healthy and disease contexts, and how these could be leveraged in the treatment of cancer.

Keywords:  Metabolism; Oocytes; Quiescence; Stem cells

DOI:  https://doi.org/10.1242/jcs.260787
Biochim Biophys Acta Mol Basis Dis. 2023 Aug 12. pii: S0925-4439(23)00212-0. [Epub ahead of print] 166846

Iron promotes glycolysis to drive colon tumorigenesis.

Zhaoli Liu, Luke Villareal, Lavanya Goodla, Hyeoncheol Kim, Daniel M Falcon, Mohammad Haneef, David R Martin, Li Zhang, Ho-Joon Lee, Daniel Kremer, Costas A Lyssiotis, Yatrik M Shah, Henry C Lin, Hui-Kuan Lin, Xiang Xue.

  Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function.

Keywords:  GLUT1; Glucose; Iron; PDH; PDHK3; Tankyrase

DOI:  https://doi.org/10.1016/j.bbadis.2023.166846
J Biol Eng. 2023 Aug 17. 17(1): 53

Cancer-on-chip: a 3D model for the study of the tumor microenvironment.

Elisa Cauli, Michela Anna Polidoro, Simona Marzorati, Claudio Bernardi, Marco Rasponi, Ana Lleo.

  The approval of anticancer therapeutic strategies is still slowed down by the lack of models able to faithfully reproduce in vivo cancer physiology. On one hand, the conventional in vitro models fail to recapitulate the organ and tissue structures, the fluid flows, and the mechanical stimuli characterizing the human body compartments. On the other hand, in vivo animal models cannot reproduce the typical human tumor microenvironment, essential to study cancer behavior and progression. This study reviews the cancer-on-chips as one of the most promising tools to model and investigate the tumor microenvironment and metastasis. We also described how cancer-on-chip devices have been developed and implemented to study the most common primary cancers and their metastatic sites. Pros and cons of this technology are then discussed highlighting the future challenges to close the gap between the pre-clinical and clinical studies and accelerate the approval of new anticancer therapies in humans.

Keywords:  Cancer-on-chip; Metastasis; Microfluidics; Organ-on-chip; Pre-clinical models; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13036-023-00372-6
Prostaglandins Leukot Essent Fatty Acids. 2023 Aug 09. pii: S0952-3278(23)00054-6. [Epub ahead of print]196 102585

Tumor microenvironment-derived monoacylglycerol lipase provokes tumor-specific immune responses and lipid profiles.

Eva Gruden, Melanie Kienzl, Carina Hasenoehrl, Arailym Sarsembayeva, Dusica Ristic, Sophie Theresa Schmid, Kathrin Maitz, Ulrike Taschler, Lisa Hahnefeld, Robert Gurke, Dominique Thomas, Julia Kargl, Rudolf Schicho.

  We recently described that monoacylglycerol lipase (MGL) is present in the tumor microenvironment (TME), increasing tumor growth. In this study we compare the implications of MGL deficiency in the TME in different tumor types. We show that subcutaneous injection of KP (KrasLSL-G12D/p53fl/fl, mouse lung adenocarcinoma) or B16-F10 cells (mouse melanoma) induced tumor growth in MGL wild type (WT) and knockout (KO) mice. MGL deficiency in the TME attenuated the growth of KP cell tumors whereas tumors from B16-F10 cells increased in size. Opposite immune cell profiles were detected between the two tumor types in MGL KO mice. In line with their anti-tumorigenic function, the number of CD8+ effector T cells and eosinophils increased in KP cell tumors of MGL KO vs. WT mice whereas their presence was reduced in B16-F10 cell tumors of MGL KO mice. Differences were seen in lipid profiles between the investigated tumor types. 2-arachidonoylglycerol (2-AG) content significantly increased in KP, but not B16-F10 cell tumors of MGL KO vs. WT mice while other endocannabinoid-related lipids remained unchanged. However, profiles of phospho- and lysophospholipids, sphingomyelins and fatty acids in KP cell tumors were clearly distinct to those measured in B16-F10 cell tumors. Our data indicate that TME-localized MGL impacts tumor growth, as well as levels of 2-AG and other lipids in a tumor specific manner.

Keywords:  (lyso)phospholipids; Endocannabinoids; Melanoma; Monoacylglycerol lipase; Non-small cell lung cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.plefa.2023.102585
Trends Cell Biol. 2023 Aug 10. pii: S0962-8924(23)00138-1. [Epub ahead of print]

Sublethal engagement of apoptotic pathways in residual cancer.

Shane T Killarney, Stephen W G Tait, Douglas R Green, Kris C Wood.

  Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical, regulated step in this apoptotic pathway. The residual cancer cells that survive treatment serve as the seeds of eventual relapse and are often functionally characterized by their transient tolerance of multiple therapeutic treatments. New studies suggest that, in these cells, a sublethal degree of MOMP, reflective of incomplete apoptotic commitment, is widely observed. Here, we review recent evidence that this sublethal MOMP drives the aggressive features of residual cancer cells while templating a host of unique vulnerabilities, highlighting how failed apoptosis may counterintuitively enable new therapeutic strategies to target residual disease (RD).

Keywords:  DNA damage response; drug-tolerant persisters; integrated stress response; sublethal MOMP

DOI:  https://doi.org/10.1016/j.tcb.2023.07.005
Transl Oncol. 2023 Aug 10. pii: S1936-5233(23)00144-4. [Epub ahead of print]37 101758

Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression.

Madhura R Pandkar, Sommya Sinha, Atul Samaiya, Sanjeev Shukla.

  Due to the enhanced glycolytic rate, cancer cells generate lactate copiously, subsequently promoting the lactylation of histones. While previous studies have explored the impact of histone lactylation in modulating gene expression, the precise role of this epigenetic modification in regulating oncogenes is largely unchartered. In this study, using breast cancer cell lines and their mutants exhibiting lactate-deficient metabolome, we have identified that an enhanced rate of aerobic glycolysis supports c-Myc expression via promoter-level histone lactylation. Interestingly, c-Myc further transcriptionally upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing of MDM4 and Bcl-x in breast cancer cells. Moreover, our results reveal that restricting the activity of critical glycolytic enzymes affects the c-Myc-SRSF10 axis to subside the proliferation of breast cancer cells. Our findings provide novel insights into the mechanisms by which aerobic glycolysis influences alternative splicing processes that collectively contribute to breast tumorigenesis. Furthermore, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis.

Keywords:  Epigenetics; Histone modifications; SRSF10; Tumor metabolism; Warburg effect; c-Myc

DOI:  https://doi.org/10.1016/j.tranon.2023.101758
Oncoimmunology. 2023 ;12(1): 2246322

TNBC-derived Gal3BP/Gal3 complex induces immunosuppression through CD45 receptor.

Annat Raiter, Julia Lipovetsky, Asaf Stenbac, Ido Lubin, Rinat Yerushalmi.

  A preliminary study investigating immunotherapy strategies for aggressive triple negative breast cancer (TNBC) revealed an overexpression of genes involved in the release of extracellular vesicles (EVs). Proteins expressed by EVs play a role in reprogramming the tumor microenvironment and impeding effective responses to immunotherapy. Galectin 3 (Gal3), found in the extracellular space of breast cancer cells, downregulates T-cell receptor expression. Gal3 binds to several receptors, including CD45, which is required for T-cell receptor activation. Previously, we reported a novel tumor escape mechanism, whereby TNBC cells suppress immune cells through CD45 intracellular signals. The objective of this study was to determine the potential association of Gal3 with TNBC-secreted EVs induction of immunosuppression via the CD45 signaling pathway. EVs were isolated from MDA-MB-231 cells and the plasma of patients with TNBC. Mass spectrometry revealed the presence of Gal3 binding protein (Gal3BP) in the isolated small EVs, which interacted with TNBC secreted Gal3. Gal3BP and Gal3 form a complex that induces a significant increase in T-regulatory cells in peripheral blood mononuclear cells (PBMCs). This increase correlates with a significant increase in suppressive interleukins 10 and 35. Blocking the CD45 receptor in PBMCs cultured with tumor-derived EVs impeded the immunosuppression exerted by the Gal3BP/Gal3 complex. This led to an increase in IFN-γ and the activation of CD4, CD8 and CD56 effector cells. This study suggests a tumor escape mechanism that may contribute to the development of a different immunotherapy strategy that complements current therapies used for TNBC.

Keywords:  Galectin 3; Galectin 3 binding protein; TNBC; immunosuppression; small extracellular vesicles

DOI:  https://doi.org/10.1080/2162402X.2023.2246322