bims-mecami 2023-04-30 papers

Issue of 2023–04–30
seven papers selected by
Oltea Sampetrean, Keio University

Int J Mol Sci. 2023 Apr 18. pii: 7463. [Epub ahead of print]24(8):

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses.

Beatrice Foglia, Marc Beltrà, Salvatore Sutti, Stefania Cannito.

Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

Keywords: HCC; TCA cycle; amino acid metabolism; fatty acid metabolism; glucose metabolism; glutamine; immune response; metabolic reprogramming; tumor microenvironment; urea cycle

DOI: https://doi.org/10.3390/ijms24087463

Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2216587120

Programmed cell death-1 receptor-mediated regulation of Tbet+NK1.1- innate lymphoid cells within the tumor microenvironment.

Jing Xuan Lim, Chester Y Lai, Grace E Mallett, David McDonald, Gillian Hulme, Stephanie Laba, Andrew Shapanis, Megan Payne, Warren Patterson, Michael Alexander, Jonathan Coxhead, Andrew Filby, Ruth Plummer, Penny E Lovat, Giuseppe Sciume, Eugene Healy, Shoba Amarnath.

Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet+NK1.1- and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1- ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1- ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet+NK1.1- ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet+NK1.1- ILCs expressed significantly increased IFNγ and granzyme B and K. Furthermore, PD-1-deficient Tbet+NK1.1- ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet+NK1.1- ILCs within the TME.

Keywords: ILC; PD-1; cSCC; melanoma

DOI: https://doi.org/10.1073/pnas.2216587120

Immunology. 2023 Apr 24.

Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression.

Shizhen Ding, Zhijie Lin, Xiaoyuan Zhang, Xiaoqing Jia, Hualing Li, Yi Fu, Xuefeng Wang, Guoqiang Zhu, Guotao Lu, Weiming Xiao, Weijuan Gong.

Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this study, more CD8+ T cells were activated to be effector T cells in ANGPTL4-/- mice. Impaired growth of tumours implanted in 3LL, B16BL6 or MC38 cells and reduced metastasis by B16F10 cells were observed in ANGPTL4-/- mice. Bone marrow (BM) transplantation experiments displayed that deficiency of ANGPTL4 in either host or BM cells promoted CD8+ T cell activation. However, ANGPTL4 deficiency in CD8+ T cells themselves showed more efficient anti-tumour activities. Recombinant ANGPTL4 protein promoted tumour growth in vivo with the less CD8+ T cell infiltration and it directly downregulated CD8+ T cell activation ex vivo. Transcriptome sequencing and metabolism analysis identified that ANGPTL4-/- CD8+ T cells increased glycolysis and decreased oxidative phosphorylation, which was dependent on the PKCζ-LKB1-AMPK-mTOR signalling axis. Reverse correlation of elevated ANGPTL4 levels in sera and tumour tissues with activated CD8+ T cells in the peripheral blood was displayed in patients with colorectal cancer. These results demonstrated that ANGPTL4 decreased immune surveillance in tumour progression by playing an immune-modulatory role on CD8+ T cells via metabolic reprogramming. Efficient blockade of ANGPTL4 expression in tumour patients would generate an effective anti-tumour effect mediated by CD8+ T cells.

Keywords: ANGPTL4; CD8; T cell; metabolism; tumour

DOI: https://doi.org/10.1111/imm.13650

Breast Cancer Res. 2023 Apr 25. 25(1): 46

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.

Soojung Lee, Nicolai J Toft, Trine V Axelsen, Maria Sofia Espejo, Tina M Pedersen, Marco Mele, Helene L Pedersen, Eva Balling, Tonje Johansen, Mark Burton, Mads Thomassen, Pernille Vahl, Peer Christiansen, Ebbe Boedtkjer.

BACKGROUND: Carbonic anhydrases catalyze CO2/HCO3- buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid-base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear.
METHODS: We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas.
RESULTS: Carbonic anhydrases-particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14-undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis.
CONCLUSIONS: We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

Keywords: Acetazolamide; Acidosis; Breast cancer; Carbonic anhydrases; ErbB2; HER2; Immuno-oncology; Metabolism; Perfusion; Tumor microenvironment

DOI: https://doi.org/10.1186/s13058-023-01644-1

Front Oncol. 2023 ;13 1155621

Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment.

María Matamala Montoya, Gijs J J van Slobbe, Jung-Chin Chang, Esther A Zaal, Celia R Berkers.

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance. Metabolic reprogramming is emerging as a hallmark of cancer that can potentially be exploited for cancer treatment. Recent studies show that metabolism is further adjusted in MM cells during the development of drug resistance. However, little is known about the role of BMSCs in inducing metabolic changes that are associated with drug resistance. In this Perspective, we summarize current knowledge concerning the metabolic reprogramming of MM, with a focus on those changes associated with drug resistance to the proteasome inhibitor Bortezomib (BTZ). In addition, we present proof-of-concept fluxomics (glucose isotope-tracing) and Seahorse data to show that co-culture of MM cells with BMSCs skews the metabolic phenotype of MM cells towards a drug-resistant phenotype, with increased oxidative phosphorylation (OXPHOS), serine synthesis pathway (SSP), TCA cycle and glutathione (GSH) synthesis. Given the crucial role of BMSCs in conveying drug resistance, insights into the metabolic interaction between MM and BMSCs may ultimately aid in the identification of novel metabolic targets that can be exploited for therapy.

Keywords: Bortezomib; bone marrow stromal cell (BMSC); cancer metabolism; drug resistance; fluxomics; metabolomics; multiple myeloma; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2023.1155621

bioRxiv. 2023 Apr 13. pii: 2023.04.12.536619. [Epub ahead of print]

Carcinoma-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment.

Emma D Wrenn, April A Apfelbaum, Erin R Rudzinski, Xuemei Deng, Wei Jiang, Sudha Sud, Raelene A Van Noord, Erika A Newman, Nicolas M Garcia, Virginia J Hoglund, Shruti S Bhise, Sami B Kanaan, Olivia G Waltner, Scott N Furlan, Elizabeth R Lawlor.

Tumor heterogeneity is a major driver of cancer progression. In epithelial-derived malignancies, carcinoma-associated fibroblasts (CAFs) contribute to tumor heterogeneity by depositing extracellular matrix (ECM) proteins that dynamically remodel the tumor microenvironment (TME). Ewing sarcomas (EwS) are histologically monomorphous, mesenchyme-derived tumors that are devoid of CAFs. Here we identify a previously uncharacterized subpopulation of transcriptionally distinct EwS tumor cells that deposit pro-tumorigenic ECM. Single cell analyses revealed that these CAF-like cells differ from bulk EwS cells by their upregulation of a matrisome-rich gene signature that is normally repressed by EWS::FLI1, the oncogenic fusion transcription factor that underlies EwS pathogenesis. Further, our studies showed that ECM-depositing tumor cells express the cell surface marker CD73, allowing for their isolation ex vivo and detection in situ. Spatial profiling of tumor xenografts and patient biopsies demonstrated that CD73 + EwS cells and tumor cell-derived ECM are prevalent along tumor borders and invasive fronts. Importantly, despite loss of EWS::FLI1-mediated gene repression, CD73 + EwS cells retain expression of EWS::FLI1 and the fusion-activated gene signature, as well as tumorigenic and proliferative capacities. Thus, EwS tumor cells can be reprogrammed to adopt CAF-like properties and these transcriptionally and phenotypically distinct cell subpopulations contribute to tumor heterogeneity by remodeling the TME.

DOI: https://doi.org/10.1101/2023.04.12.536619

JCI Insight. 2023 Apr 24. pii: e165419. [Epub ahead of print]8(8):

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.

Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

Keywords: Genetic variation; Lung cancer; Metabolism; Molecular genetics; Oncology

DOI: https://doi.org/10.1172/jci.insight.165419