bims-mecami 2022-12-04 papers

Issue of 2022–12–04
seven papers selected by
Linda Chan, Yale University

Cancer Discov. 2022 Dec 02. OF1

Ferroptosis Inhibition Blocks Tumor Growth by Restoring T-cell Function.

Ferroptosis of immunosuppressive neutrophils in the tumor microenvironment blocks antitumor immunity.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-210

Nat Commun. 2022 Nov 28. 13(1): 7338

Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.

Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.

Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.

DOI: https://doi.org/10.1038/s41467-022-34632-8

Nat Rev Endocrinol. 2022 Nov 29.

Metabolic determinants of tumour initiation.

Julia S Brunner, Lydia W S Finley.

Tumours exhibit notable metabolic alterations compared with their corresponding normal tissue counterparts. These metabolic alterations can support anabolic growth, enable survival in hostile environments and regulate gene expression programmes that promote malignant progression. Whether these metabolic changes are selected for during malignant transformation or can themselves be drivers of tumour initiation is unclear. However, intriguingly, many of the major bottlenecks for tumour initiation - control of cell fate, survival and proliferation - are all amenable to metabolic regulation. In this article, we review evidence demonstrating a critical role for metabolic pathways in processes that support the earliest stages of tumour development. We discuss how cell-intrinsic factors, such as the cell of origin or transforming oncogene, and cell-extrinsic factors, such as local nutrient availability, promote or restrain tumour initiation. Deeper insight into how metabolic pathways control tumour initiation will improve our ability to design metabolic interventions to limit tumour incidence.

DOI: https://doi.org/10.1038/s41574-022-00773-5

Cancer Metab. 2022 Dec 01. 10(1): 21

Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.

Xinyi Zhang, Alexandra A Halberstam, Wanling Zhu, Brooks P Leitner, Durga Thakral, Marcus W Bosenberg, Rachel J Perry.

BACKGROUND: Research about tumor "metabolic flexibility"-the ability of cells to toggle between preferred nutrients depending on the metabolic context-has largely focused on obesity-associated cancers. However, increasing evidence for a key role for nutrient competition in the tumor microenvironment, as well as for substrate regulation of immune function, suggests that substrate metabolism deserves reconsideration in immunogenic tumors that are not strongly associated with obesity.
METHODS: We compare two murine models: immunologically cold YUMM1.7 and immunologically-hot YUMMER1.7. We utilize stable isotope and radioisotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics analyses to comprehensively probe substrate preference in YUMM1.7 and YUMMER1.7 cells, with a subset of studies on the impact of available metabolites across a panel of five additional melanoma cell lines. We analyze bulk RNA-seq data and identify increased expression of amino acid and glucose metabolism genes in YUMMER1.7. Finally, we analyze melanoma patient RNA-seq data to identify potential prognostic predictors rooted in metabolism.
RESULTS: We demonstrate using stable isotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics that immunologically-hot melanoma utilizes more glutamine than immunologically-cold melanoma in vivo and in vitro. Analyses of human melanoma RNA-seq data demonstrate that glutamine transporter and other anaplerotic gene expression positively correlates with lymphocyte infiltration and function.
CONCLUSIONS: Here, we highlight the importance of understanding metabolism in non-obesity-associated cancers, such as melanoma. This work advances the understanding of the correlation between metabolism and immunogenicity in the tumor microenvironment and provides evidence supporting metabolic gene expression as potential prognostic factors of melanoma progression and may inform investigations of adjunctive metabolic therapy in melanoma.
TRIAL REGISTRATION: Deidentified data from The Cancer Genome Atlas were analyzed.

Keywords: Amino acid; Glucose; Melanoma; Tumor metabolism; Tumor microenvironment

DOI: https://doi.org/10.1186/s40170-022-00296-7

Mol Cell. 2022 Dec 01. pii: S1097-2765(22)01067-X. [Epub ahead of print]82(23): 4407-4409

D-2HG comes out of its shell: Metabolic effects on the immune environment.

Juan Manuel Schvartzman, Andrew M Intlekofer.

A recent study by Notarangelo et al.1 highlights the potential for tumor-derived D-2HG to inhibit neighboring T cell function through a novel mechanism.

DOI: https://doi.org/10.1016/j.molcel.2022.11.005

Cancer Lett. 2022 Nov 25. pii: S0304-3835(22)00507-9. [Epub ahead of print]554 216020

mTOR inhibitor, gemcitabine and PD-L1 antibody blockade combination therapy suppresses pancreatic cancer progression via metabolic reprogramming and immune microenvironment remodeling in Trp53flox/+LSL-KrasG12D/+Pdx-1-Cre murine models.

Jiangdong Qiu, Mengyu Feng, Gang Yang, Zhe Cao, Yueze Liu, Lei You, Taiping Zhang.

OBJECTIVE: Resistance to immunotherapy and chemotherapy hinders the prognosis of pancreatic cancer(PC). We hypothesized that the combination of mTOR inhibitor sirolimus and gemcitabine would change the metabolic landscape of PC and enhance the anti-PD-L1 therapy.
METHODS: In KPC mice, the following regimens were administered and tumor growth inhibition rates(TGI%) were calculated: sirolimus(S), PD-L1 antibody(P), gemcitabine(G), sirolimus + PD-L1 antibody(SP), sirolimus + gemcitabine(SG), PD-L1 + gemcitabine(PG) and sirolimus + PD-L1 antibody + gemcitabine(SPG). The metabolic changes of tumors were identified by LC-MS and subpopulations of immune cells were measured by flow cytometry. Sirolimus treated macrophages were co-cultured with PC cells in vitro, and the metabolic changes of macrophages and tumor cells as well as tumor cells' viability were detected.
RESULTS: The monotherapy of S, P and G didn't inhibit tumor growth significantly. The combination of SP, PG and SG didn't improve the TGI% significantly compared with monotherapy. However, the TGI% of SPG combination was higher than other groups. The proportion of CD68+ macrophages increased in the peripheral blood and CD8+ T cells decreased in the tumor tissues after SPG treatment. LC-MS identified 42 differential metabolites caused by sirolimus in SPG group, among which 10 metabolites had potential effects on macrophages. Sirolimus treated M1 and M2 macrophages inhibited the proliferation of tumor cells and decreased tumor cells' glycolysis. The glycolysis of M2 macrophages was increased by sirolimus.
CONCLUSIONS: mTOR inhibitor can change the immune microenvironment of PC via metabolic reprogramming, thus promoting the efficacy of PD-L1 blockade when combined with gemcitabine.

Keywords: KPC murine Model; Macrophage; Metabolic reprogramming; Pancreatic cancer; mTOR inhibitor

DOI: https://doi.org/10.1016/j.canlet.2022.216020

Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01606-0. [Epub ahead of print]41(9): 111728

BRAFV600E in colorectal cancer reduces sensitivity to oxidative stress and promotes site-specific metastasis by stimulating glutathione synthesis.

Jamila Laoukili, Susanne van Schelven, Emre Küçükköse, André Verheem, Kaitlyn Goey, Miriam Koopman, Inne Borel Rinkes, Onno Kranenburg.

The presence of BRAFV600E in colorectal cancer (CRC) is associated with a higher chance of distant metastasis. Oxidative stress in disseminated tumor cells limits metastatic capacity. To study the relationship between BRAFV600E, sensitivity to oxidative stress, and metastatic capacity in CRC, we use patient-derived organoids (PDOs) and tissue samples. BRAFV600E tumors and PDOs express high levels of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Deletion of GCL in BRAFV600E PDOs strongly reduces their capacity to form distant liver and lung metastases but does not affect peritoneal metastasis outgrowth. Vice versa, the glutathione precursor N-acetyl-cysteine promotes organ-site-specific metastasis in the liver and the lungs but not in the peritoneum. BRAFV600E confers resistance to pharmacologically induced oxidative stress in vitro, which is partially overcome by treatment with the BRAF-inhibitor vemurafenib. We conclude that GCL-driven glutathione synthesis protects BRAFV600E-expressing tumors from oxidative stress during distant metastasis to the liver and the lungs.

Keywords: BRAF(V600E); CP: Cancer; colorectal; glutathione; metastasis; metastatic organotropsim; oxidative stress

DOI: https://doi.org/10.1016/j.celrep.2022.111728