bims-mecami 2023-05-07 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2023‒05‒07
six papers selected by
Oltea Sampetrean, Keio University

Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.
Imaging the metabolic reprograming of fatty acid synthesis pathway enables new diagnostic and therapeutic opportunity for breast cancer.
Redox homeostasis and beyond: The role of wild-type Isocitrate Dehydrogenases for the pathogenesis of Glioblastoma.
EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.
Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states.

Exp Mol Med. 2023 May 01.

Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.

Steven W Wall, Lilia Sanchez, Kelly Scribner Tuttle, Scott J Pearson, Shivatheja Soma, Garhett L Wyatt, Hannah N Carter, Ramsey M Jenschke, Lin Tan, Sara A Martinez, Philip L Lorenzi, Vishal M Gohil, Monique Rijnkels, Weston W Porter.

Dysregulation of cellular metabolism is a hallmark of breast cancer progression and is associated with metastasis and therapeutic resistance. Here, we show that the breast tumor suppressor gene SIM2 promotes mitochondrial oxidative phosphorylation (OXPHOS) using breast cancer cell line models. Mechanistically, we found that SIM2s functions not as a transcription factor but localizes to mitochondria and directly interacts with the mitochondrial respiratory chain (MRC) to facilitate functional supercomplex (SC) formation. Loss of SIM2s expression disrupts SC formation through destabilization of MRC Complex III, leading to inhibition of electron transport, although Complex I (CI) activity is retained. A metabolomic analysis showed that knockout of SIM2s leads to a compensatory increase in ATP production through glycolysis and accelerated glutamine-driven TCA cycle production of NADH, creating a favorable environment for high cell proliferation. Our findings indicate that SIM2s is a novel stabilizing factor required for SC assembly, providing insight into the impact of the MRC on metabolic adaptation and breast cancer progression.

DOI: https://doi.org/10.1038/s12276-023-00996-0
Cancer Cell Int. 2023 Apr 29. 23(1): 83

Imaging the metabolic reprograming of fatty acid synthesis pathway enables new diagnostic and therapeutic opportunity for breast cancer.

Fukai Wang, Shuangshuang Ma, Panpan Chen, Yuhao Han, Zhaoyun Liu, Xinzhao Wang, Chenglong Sun, Zhiyong Yu.

  BACKGROUND: Reprogrammed metabolic network is a key hallmark of cancer. Profiling cancer metabolic alterations with spatial signatures not only provides clues for understanding cancer biochemical heterogeneity, but also helps to decipher the possible roles of metabolic reprogramming in cancer development.METHODS: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique was used to characterize the expressions of fatty acids in breast cancer tissues. Specific immunofluorescence staining was further carried out to investigate the expressions of fatty acid synthesis-related enzymes.
RESULTS: The distributions of 23 fatty acids in breast cancer tissues have been mapped, and the levels of most fatty acids in cancer tissues are significantly higher than those in adjacent normal tissues. Two metabolic enzymes, fatty acid synthase (FASN) and acetyl CoA carboxylase (ACC), which being involved in the de novo synthesis of fatty acid were found to be up-regulated in breast cancer. Targeting the up-regulation of FASN and ACC is an effective approach to limiting the growth, proliferation, and metastasis of breast cancer cells.
CONCLUSIONS: These spatially resolved findings enhance our understanding of cancer metabolic reprogramming and give an insight into the exploration of metabolic vulnerabilities for better cancer treatment.

Keywords:  Breast cancer; Diagnosis and therapy; Fatty acid synthesis pathway; Mass spectrometry imaging; Metabolic reprograming

DOI:  https://doi.org/10.1186/s12935-023-02908-8
Antioxid Redox Signal. 2023 May 03.

Redox homeostasis and beyond: The role of wild-type Isocitrate Dehydrogenases for the pathogenesis of Glioblastoma.

Alexander H Stegh, Craig Horbinski, Kevin Murnan.

SIGNIFICANCE: Glioblastoma is an aggressive and devastating brain tumor characterized by a dismal prognosis and resistance to therapeutic intervention. To support catabolic processes critical for unabated cellular growth and defend against harmful reactive oxygen species, glioblastoma tumors upregulate the expression of wild-type Isocitrate Dehydrogenases (IDHs). IDH enzymes catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), NAD(P)H, and CO2. On molecular levels, IDHs epigenetically control gene expression through effects on α-KG-dependent dioxygenases, maintain redox balance, and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis.RECENT ADVANCES: While gain-of-function mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effects, recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to glioblastoma progression.
CRITICAL ISSUES: Here, we will discuss molecular mechanisms of how wild-type IDHs control glioma pathogenesis, including the regulation of oxidative stress and de novo lipid biosynthesis, and provide an overview of current and future research directives that aim to fully characterize wild-type IDH-driven metabolic reprogramming and its contribution to the pathogenesis of glioblastoma.
FUTURE DIRECTIONS: Future studies are required to further dissect mechanisms of metabolic and epigenomic reprogramming in tumors and the tumor microenvironment, and to develop pharmacological approaches to inhibit IDH function.

DOI: https://doi.org/10.1089/ars.2023.0262
bioRxiv. 2023 Apr 17. pii: 2023.04.15.536974. [Epub ahead of print]

EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.

Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Kacie A Traina, Camila Robles-Oteíza, Deborah Ayeni, Elizabeth M Kwong, Stellar R Levy, Mathew Nobari, George Z Cheng, Reuben Shaw, Sandra L Leibel, Christian M Metallo, Katerina Politi, Susan M Kaech.

The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand mechanisms governing local immunosuppression. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophages (TA-AM) to proliferate and support tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF-PPARγ signaling and inhibition of airway GM-CSF or PPARγ in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases T cell effector functions. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how such cancer cells can metabolically co-opt TA-AMs through GM-CSF-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.

DOI: https://doi.org/10.1101/2023.04.15.536974
bioRxiv. 2023 Apr 17. pii: 2023.04.15.536946. [Epub ahead of print]

Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.

Mengdi Guo, Diala Abd-Rabbo, Bruna Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks.

CD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (T TS ) cells during cancer development is still unclear. We demonstrate that CD4 T TS cells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 T TS cells and previously defined exhaustion programs, CD4 T TS cell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 T TS cell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 T TS cells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 T TS cells to favor tumor progression.

DOI: https://doi.org/10.1101/2023.04.15.536946
Nat Commun. 2023 May 04. 14(1): 2586

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states.

Osama Al-Dalahmah, Michael G Argenziano, Adithya Kannan, Aayushi Mahajan, Julia Furnari, Fahad Paryani, Deborah Boyett, Akshay Save, Nelson Humala, Fatima Khan, Juncheng Li, Hong Lu, Yu Sun, John F Tuddenham, Alexander R Goldberg, Athanassios Dovas, Matei A Banu, Tejaswi Sudhakar, Erin Bush, Andrew B Lassman, Guy M McKhann, Brian J A Gill, Brett Youngerman, Michael B Sisti, Jeffrey N Bruce, Peter A Sims, Vilas Menon, Peter Canoll.

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional 'tissue-states' defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

DOI: https://doi.org/10.1038/s41467-023-38186-1