bims-mecami 2023-06-18 papers

Issue of 2023–06–18
seven papers selected by
Oltea Sampetrean, Keio University

Front Oncol. 2023 ;13 1223630

Editorial: Rising stars in cancer metabolism 2022.

Jose Luis Izquierdo-Garcia, Domenica Scumaci.

Keywords: glutamine metabolism; metabolic reprogramming; metabolic symbiosis; metabolism and chemoresistance; metabolism and redox homeostasis; personalized medicine

DOI: https://doi.org/10.3389/fonc.2023.1223630

Cell Metab. 2023 Jun 07. pii: S1550-4131(23)00185-7. [Epub ahead of print]

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

Miriam Ferrer, Nicholas Mourikis, Emma E Davidson, Sam O Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Qing Gao, Thomas R Flint, Lisa Young, Claire M Connell, Michael J Lukey, Marcus D Goncalves, Eileen P White, Ashok R Venkitaraman, Tobias Janowitz.

Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

Keywords: GDF-15; IL-6; NADPH; cachexia; cancer; corticosterone; ferroptosis; ketogenic diet; lipid peroxidation; steroid

DOI: https://doi.org/10.1016/j.cmet.2023.05.008

Oncol Res. 2022 ;30(5): 231-242

The remodeling roles of lipid metabolism in colorectal cancer cells and immune microenvironment.

Jiateng Zhong, Jingyu Guo, Xinyu Zhang, Shuang Feng, Wenyu DI, Yanling Wang, Huifang Zhu.

Lipid is a key component of plasma membrane, which plays an important role in the regulation of various cell biological behaviors, including cell proliferation, growth, differentiation and intracellular signal transduction. Studies have shown that abnormal lipid metabolism is involved in many malignant processes, including colorectal cancer (CRC). Lipid metabolism in CRC cells can be regulated not only by intracellular signals, but also by various components in the tumor microenvironment, including various cells, cytokines, DNA, RNA, and nutrients including lipids. In contrast, abnormal lipid metabolism provides energy and nutrition support for abnormal malignant growth and distal metastasis of CRC cells. In this review, we highlight the remodeling roles of lipid metabolism crosstalk between the CRC cells and the components of tumor microenvironment.

Keywords: Colorectal cancer; Lipid metabolism; Tumor microenvironment (TME)

DOI: https://doi.org/10.32604/or.2022.027900

Cancer Lett. 2023 Jun 12. pii: S0304-3835(23)00218-5. [Epub ahead of print] 216267

Lipid metabolism reprogramming of CD8+ T cell and therapeutic implications in cancer.

Runxian Wang, Zhenya Liu, Zhiyao Fan, Hanxiang Zhan.

Effector, memory and exhaustion are three phenotypes of CD8+ T cell. In tumor microenvironment (TME), metabolism dysfunction of the three should take the blame for immune escape. Against background of CD8+ T cell in normal development, multiple determinants in TME, including nutrition competition, PD-1 signals and other cancer- CD8+ T cell interaction, cause metabolism reprograming, including failure in energy metabolism and other abnormal lipid metabolism. Further, incompatibility of different CD8+ T cell metabolism pattern results in unresponsiveness of immune checkpoint blockade (ICB). Therefore, combination of ICB and drugs aiming at abnormal lipid metabolism provides promising direction to improve cancer therapy.

Keywords: Cholesterol; Energy metabolism; Immune checkpoint blockade; Lipid peroxidation; Metabolism regulating drug; Mitochondria

DOI: https://doi.org/10.1016/j.canlet.2023.216267

Cancer Cell. 2023 Jun 12. pii: S1535-6108(23)00182-4. [Epub ahead of print]

MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma.

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.

Keywords: LKB1; MCT4; PD-1; T cell activation; immunotherapy resistance; lactate; lung adenocarcinoma; macrophage polarization; metabolism

DOI: https://doi.org/10.1016/j.ccell.2023.05.015

Front Oncol. 2023 ;13 1223025

Editorial: The impact of alkalizing the acidic tumor microenvironment to improve efficacy of cancer treatment.

Reo Hamaguchi, Shinji Uemoto, Hiromi Wada.

Keywords: alkalization therapy; cancer; cancer metabolism; multi-drug resistance; pH; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2023.1223025

Front Immunol. 2023 ;14 1190810

Short chain fatty acids prime colorectal cancer cells to activate antitumor immunity.

Courtney Mowat, Jasmine Dhatt, Ilsa Bhatti, Angela Hamie, Kristi Baker.

Introduction: Colorectal cancer (CRC) is a leading cause of death worldwide and its growth can either be promoted or inhibited by the metabolic activities of intestinal microbiota. Short chain fatty acids (SCFAs) are microbial metabolites with potent immunoregulatory properties yet there is a poor understanding of how they directly regulate immune modulating pathways within the CRC cells.
Methods: We used engineered CRC cell lines, primary organoid cultures, orthotopic in vivo models, and patient CRC samples to investigate how SCFA treatment of CRC cells regulates their ability to activate CD8+ T cells.
Results: CRC cells treated with SCFAs induced much greater activation of CD8+ T cells than untreated CRC cells. CRCs exhibiting microsatellite instability (MSI) due to inactivation of DNA mismatch repair were much more sensitive to SCFAs and induced much greater CD8+ T cell activation than chromosomally instable (CIN) CRCs with intact DNA repair, indicating a subtype-dependent response to SCFAs. This was due to SCFA-induced DNA damage that triggered upregulation of chemokine, MHCI, and antigen processing or presenting genes. This response was further potentiated by a positive feedback loop between the stimulated CRC cells and activated CD8+ T cells in the tumor microenvironment. The initiating mechanism in the CRCs was inhibition of histone deacetylation by the SCFAs that triggered genetic instability and led to an overall upregulation of genes associated with SCFA signaling and chromatin regulation. Similar gene expression patterns were found in human MSI CRC samples and in orthotopically grown MSI CRCs independent of the amount of SCFA producing bacteria in the intestine.
Discussion: MSI CRCs are widely known to be more immunogenic than CIN CRCs and have a much better prognosis. Our findings indicate that a greater sensitivity to microbially produced SCFAs contributes to the successful activation of CD8+ T cells by MSI CRCs, thereby identifying a mechanism that could be therapeutically targeted to improve antitumor immunity in CIN CRCs.

Keywords: HDAC; antitumor immunity; colorectal cancer; microbiota; microsatellite instability; short chain fatty acid (SCFA)

DOI: https://doi.org/10.3389/fimmu.2023.1190810