bims-mecami 2022-11-06 papers

Issue of 2022–11–06
nine papers selected by
Linda Chan, Yale University

Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00451-X. [Epub ahead of print]34(11): 1617-1619

Targeting PDAC metabolism: Environment determines what has GOT2 give.

Metabolic disruption is a mainstay of cancer therapy, prompting research aimed at identifying novel metabolic targets. Despite strong effects observed in culture, three recent studies found pancreatic tumors are refractory to disruption of the metabolic enzyme GOT2, revealing complex interactions within the tumor microenvironment that bypass its conventional metabolic roles.

DOI: https://doi.org/10.1016/j.cmet.2022.09.027

Semin Cancer Biol. 2022 Oct 28. pii: S1044-579X(22)00204-8. [Epub ahead of print]86(Pt 3): 1216-1230

Tumor glycolysis, an essential sweet tooth of tumor cells.

Sumana Paul, Saikat Ghosh, Sushil Kumar.

Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.

Keywords: Cancer metabolism; Lactate; Metastasis; Tumor glycolysis; metabolic adaptations

DOI: https://doi.org/10.1016/j.semcancer.2022.09.007

Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00460-0. [Epub ahead of print]34(11): 1613-1615

Kir2.1 channel: Macrophage plasticity in tumor microenvironment.

Umar Al-Sheikh, Lijun Kang.

Diverse ion channels have dysregulated functional expression in the tumor microenvironment (TME). In this issue of Cell Metabolism, Chen et al. reveal that high intratumoral K+ ions restrict the plasticity of tumor-associated macrophages (TAMs). Inhibition of the Kir2.1 potassium channel induced metabolic reprogramming and repolarization of pro-tumor M2-TAMs to tumoricidal M1-like states.

DOI: https://doi.org/10.1016/j.cmet.2022.10.009

Front Immunol. 2022 ;13 1030831

Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy.

Yi Lin, Xiaoting Zhou, Yanghong Ni, Xia Zhao, Xiao Liang.

Ovarian cancer is the most lethal gynecologic tumor, with the highest mortality rate. Numerous studies have been conducted on the treatment of ovarian cancer in the hopes of improving therapeutic outcomes. Immune cells have been revealed to play a dual function in the development of ovarian cancer, acting as both tumor promoters and tumor suppressors. Increasingly, the tumor immune microenvironment (TIME) has been proposed and confirmed to play a unique role in tumor development and treatment by altering immunosuppressive and cytotoxic responses in the vicinity of tumor cells through metabolic reprogramming. Furthermore, studies of immunometabolism have provided new insights into the understanding of the TIME. Targeting or activating metabolic processes of the TIME has the potential to be an antitumor therapy modality. In this review, we summarize the composition of the TIME of ovarian cancer and its metabolic reprogramming, its relationship with drug resistance in ovarian cancer, and recent research advances in immunotherapy.

Keywords: immunotherapy; metabolic reprogramming; metabolism; ovarian cancer; tumor immune microenvironment

DOI: https://doi.org/10.3389/fimmu.2022.1030831

Front Immunol. 2022 ;13 990794

Metabolic requirements of Th17 cells and of B cells: Regulation and defects in health and in inflammatory diseases.

Jonas Bystrom, Taher E Taher, Sian M Henson, David J Gould, Rizgar A Mageed.

The immune system protects from infections and cancer through complex cellular networks. For this purpose, immune cells require well-developed mechanisms of energy generation. However, the immune system itself can also cause diseases when defective regulation results in the emergence of autoreactive lymphocytes. Recent studies provide insights into how differential patterns of immune cell responses are associated with selective metabolic pathways. This review will examine the changing metabolic requirements of Th17 cells and of B cells at different stages of their development and activation. Both cells provide protection but can also mediate diseases through the production of autoantibodies and the production of proinflammatory mediators. In health, B cells produce antibodies and cytokines and present antigens to T cells to mount specific immunity. Th17 cells, on the other hand, provide protection against extra cellular pathogens at mucosal surfaces but can also drive chronic inflammation. The latter cells can also promote the differentiation of B cells to plasma cells to produce more autoantibodies. Metabolism-regulated checkpoints at different stages of their development ensure the that self-reactive B cells clones and needless production of interleukin (IL-)17 are limited. The metabolic regulation of the two cell types has some similarities, e.g. the utility of hypoxia induced factor (HIF)1α during low oxygen tension, to prevent autoimmunity and regulate inflammation. There are also clear differences, as Th17 cells only are vulnerable to the lack of certain amino acids. B cells, unlike Th17 cells, are also dependent of mechanistic target of rapamycin 2 (mTORC2) to function. Significant knowledge has recently been gained, particularly on Th17 cells, on how metabolism regulates these cells through influencing their epigenome. Metabolic dysregulation of Th17 cells and B cells can lead to chronic inflammation. Disease associated alterations in the genome can, in addition, cause dysregulation to metabolism and, thereby, result in epigenetic alterations in these cells. Recent studies highlight how pathology can result from the cooperation between the two cell types but only few have so far addressed the key metabolic alterations in such settings. Knowledge of the impact of metabolic dysfunction on chronic inflammation and pathology can reveal novel therapeutic targets to treat such diseases.

Keywords: B cells; OXPHOS; Th17 cells; autoimmunity; epigenetics; mTORC; metabolism

DOI: https://doi.org/10.3389/fimmu.2022.990794

Annu Rev Pathol. 2022 Nov 02.

Metabolism and Colorectal Cancer.

Joseph C Sedlak, Ömer H Yilmaz, Jatin Roper.

Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathmechdis-031521-041113

Trends Cell Biol. 2022 Oct 31. pii: S0962-8924(22)00231-8. [Epub ahead of print]

Plasticity of cancer invasion and energy metabolism.

Maria Parlani, Carolina Jorgez, Peter Friedl.

Energy deprivation is a frequent adverse event in tumors that is caused by mutations, malperfusion, hypoxia, and nutrition deficit. The resulting bioenergetic stress leads to signaling and metabolic adaptation responses in tumor cells, secures survival, and adjusts migration activity. The kinetic responses of cancer cells to energy deficit were recently identified, including a switch of invasive cancer cells to energy-conservative amoeboid migration and an enhanced capability for distant metastasis. We review the energy programs employed by different cancer invasion modes including collective, mesenchymal, and amoeboid migration, as well as their interconversion in response to energy deprivation, and we discuss the consequences for metastatic escape. Understanding the energy requirements of amoeboid and other dissemination strategies offers rationales for improving therapeutic targeting of metastatic cancer progression.

Keywords: amoeboid migration; cellular bioenergetics; metabolic stress; migration plasticity

DOI: https://doi.org/10.1016/j.tcb.2022.09.009

Trends Immunol. 2022 Oct 29. pii: S1471-4906(22)00213-7. [Epub ahead of print]

Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.

Petya Apostolova, Erika L Pearce.

Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8+ T cells should be pursued to boost anti-tumor immunity.

DOI: https://doi.org/10.1016/j.it.2022.10.005

Front Immunol. 2022 ;13 932055

Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies.

Marek Jedlička, Tereza Feglarová, Lucie Janstová, Marcela Hortová-Kohoutková, Jan Frič.

Recent findings about the new roles of lactate have changed our understanding of this end product of glycolysis or fermentation that was once considered only a waste product. It is now well accepted that lactate acts as a signaling molecule and fuel source for cancer cells in a glucose-restricted environment. Moreover, lactate and lactate dehydrogenase are markers of poor prognosis of many cancers and regulate many functions of immune cells. The presence of lactate in the tumor microenvironment (TME) leads to polarization of the immunosuppressive phenotypes of dendritic cells and impairs the cytotoxic abilities of T cells and NK cells, and as such lactate is a major obstacle to immune-cell effector functions and the efficacy of cell-based immunotherapies. Emerging evidence suggests that lactate in the TME might be a novel therapeutic target to enhance the immunotherapeutic potential of cell-based therapies. This review describes our current understanding of the role of lactate in tumor biology, including its detrimental effects on cell-based immunotherapy in cancer. We also highlight how the role of lactate in the TME must be considered when producing cell therapies designed for adoptive transfer and describe how targeted modulation of lactate in the TME might boost immune-cell functions and positively impact cellular immunotherapy, with a focus on NK cell.

Keywords: NK cell; T cell; cytotoxicity; immunometabolism; immunosuppression,; immunotherapy; lactate

DOI: https://doi.org/10.3389/fimmu.2022.932055