bims-mecami 2022-10-02 papers

Issue of 2022–10–02
six papers selected by
Linda Chan, Yale University

Trends Cancer. 2022 Sep 21. pii: S2405-8033(22)00195-9. [Epub ahead of print]

GOT2 consider the tumor microenvironment.

To thrive in a hypoxic and nutrient-limited tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells rewire their metabolism. Understanding PDAC cell metabolism may uncover vulnerabilities that can be targeted for improved therapy. Three recent studies find that the PDAC tumor microenvironment modulates the functional consequences of depleting the mitochondrially localized aspartate transaminase GOT2, thus providing new insights into the metabolism of this lethal cancer.

DOI: https://doi.org/10.1016/j.trecan.2022.09.004

J Biomed Sci. 2022 Sep 26. 29(1): 74

Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend?

Cheng-Liang Kuo, Ananth Ponneri Babuharisankar, Ying-Chen Lin, Hui-Wen Lien, Yu Kang Lo, Han-Yu Chou, Vidhya Tangeda, Li-Chun Cheng, An Ning Cheng, Alan Yueh-Luen Lee.

The major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.

Keywords: Cisplatin resistance; Combination cancer immunotherapy; Hypoxia; Immunoescape; Inflammation; Lon protease (LonP1); Mitochondrial chaperone; Mitochondrial reactive oxygen species (mtROS); Tumor microenvironment

DOI: https://doi.org/10.1186/s12929-022-00859-2

Front Oncol. 2022 ;12 984560

The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies.

Danting Wang, Qizhen Ye, Haochen Gu, Zhigang Chen.

Aberrant lipid metabolism is nonnegligible for tumor cells to adapt to the tumor microenvironment (TME). It plays a significant role in the amount and function of immune cells, including tumor-associated macrophages, T cells, dendritic cells and marrow-derived suppressor cells. It is well-known that the immune response in TME is suppressed and lipid metabolism is closely involved in this process. Immunotherapy, containing anti-PD1/PDL1 therapy and adoptive T cell therapy, is a crucial clinical cancer therapeutic strategy nowadays, but they display a low-sensibility in certain cancers. In this review, we mainly discussed the importance of lipid metabolism in the formation of immunosuppressive TME, and explored the effectiveness and sensitivity of immunotherapy treatment by regulating the lipid metabolism.

Keywords: immune cells; immunotherapy; lipid metabolism; microenvironment; tumor

DOI: https://doi.org/10.3389/fonc.2022.984560

Front Oncol. 2022 ;12 980620

Ferroptosis: A potential opportunity for intervention of pre-metastatic niche.

Shenghua Zhuo, Liangwang Yang, Shenbo Chen, Caiying Tang, Weicheng Li, Zhenzhong Gao, Jigao Feng, Kun Yang.

It is widely thought that the tumor microenvironment (TME) provides the "soil" for malignant tumors to survive. Prior to metastasis, the interaction at the host site between factors secreted by primary tumors, bone-marrow-derived cells, with stromal components initiates and establishes a pre-metastatic niche (PMN) characterized by immunosuppression, inflammation, angiogenesis and vascular permeability, as well as lymphangiogenesis, reprogramming and organotropism. Ferroptosis is a non-apoptotic cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Ferroptotic cancer cells release various signal molecules into the TME to either suppress or promote tumor progression. This review highlights the important role played by ferroptosis in PMN, focusing on the relationship between ferroptosis and PMN characteristics, and discusses future research directions.

Keywords: ferroptosis; immune escape; pre-metastatic niche; therapeutic strategies; tumor

DOI: https://doi.org/10.3389/fonc.2022.980620

Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01256-6. [Epub ahead of print]40(13): 111415

De novo sphingolipid biosynthesis necessitates detoxification in cancer cells.

Meghan E Spears, Namgyu Lee, Sunyoung Hwang, Sung Jin Park, Anne E Carlisle, Rui Li, Mihir B Doshi, Aaron M Armando, Jenny Gao, Karl Simin, Lihua Julie Zhu, Paul L Greer, Oswald Quehenberger, Eduardo M Torres, Dohoon Kim.

Sphingolipids play important signaling and structural roles in cells. Here, we find that during de novo sphingolipid biosynthesis, a toxic metabolite is formed with critical implications for cancer cell survival. The enzyme catalyzing the first step in this pathway, serine palmitoyltransferase complex (SPT), is upregulated in breast and other cancers. SPT is dispensable for cancer cell proliferation, as sphingolipids can be salvaged from the environment. However, SPT activity introduces a liability as its product, 3-ketodihydrosphingosine (3KDS), is toxic and requires clearance via the downstream enzyme 3-ketodihydrosphingosine reductase (KDSR). In cancer cells, but not normal cells, targeting KDSR induces toxic 3KDS accumulation leading to endoplasmic reticulum (ER) dysfunction and loss of proteostasis. Furthermore, the antitumor effect of KDSR disruption can be enhanced by increasing metabolic input (via high-fat diet) to allow greater 3KDS production. Thus, de novo sphingolipid biosynthesis entails a detoxification requirement in cancer cells that can be therapeutically exploited.

Keywords: CP: Cancer; CP: Metabolism; cancer metabolism; cancer therapy; endoplasmic reticulum; ketodihydrosphingosine reductase; serine palmitoyltransferase

DOI: https://doi.org/10.1016/j.celrep.2022.111415

Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2123231119

Dual roles of β-arrestin 1 in mediating cell metabolism and proliferation in gastric cancer.

Huan Yu, Man Wang, Ting Zhang, Lihua Cao, Zhongwu Li, Yang Du, Yanru Hai, Xiangyu Gao, Jiafu Ji, Jianmin Wu.

β-Arrestin 1 (ARRB1) has been recognized as a multifunctional adaptor protein in the last decade, beyond its original role in desensitizing G protein-coupled receptor signaling. Here, we identify that ARRB1 plays essential roles in mediating gastric cancer (GC) cell metabolism and proliferation, by combining cohort analysis and functional investigation using patient-derived preclinical models. Overexpression of ARRB1 was associated with poor outcome of GC patients and knockdown of ARRB1 impaired cell proliferation both ex vivo and in vivo. Intriguingly, ARRB1 depicted diverse subcellular localizations during a passage of organoid cultures (7 d) to exert dual functions. Further analysis revealed that nuclear ARRB1 binds with transcription factor E2F1 triggering up-regulation of proliferative genes, while cytoplasmic ARRB1 modulates metabolic flux by binding with the pyruvate kinase M2 isoform (PKM2) and hindering PKM2 tetramerization, which reduces pyruvate kinase activity and leads to cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis. As ARRB1 localization was shown mostly in the cytoplasm in human GC samples, therapeutic potential of the ARRB1-PKM2 axis was tested, and we found tumor proliferation could be attenuated by the PKM2 activator DASA-58, especially in ARRB1high organoids. Together, the data in our study highlight a spatiotemporally dependent role of ARRB1 in mediating GC cell metabolism and proliferation and implies reactivating PKM2 may be a promising therapeutic strategy in a subset of GC patients.

Keywords: ARRB1; PKM2; cell proliferation; gastric cancer; metabolic reprogramming

DOI: https://doi.org/10.1073/pnas.2123231119