bims-meluca 2021-05-23 papers

Mol Cell Proteomics. 2021 May 13. pii: S1535-9476(21)00068-2. [Epub ahead of print] 100095

Adipose Triglyceride Lipase Loss Promotes a Metabolic Switch in A549 Non-Small Cell Lung Cancer Cell Spheroids.

Sophie Honeder, Tamara Tomin, Laura Nebel, Jürgen Gindlhuber, Katarina Fritz-Wallace, Maximilian Schinagl, Christoph Heininger, Matthias Schittmayer, Nassim Ghaffari-Tabrizi-Wizsy, Ruth Birner-Gruenberger.

Cancer cells undergo complex metabolic adaptations in order to survive and thrive in challenging environments. This is particularly prominent for solid tumors, where cells in the core of the tumor are under severe hypoxia and nutrient deprivation. However, such conditions are often not recapitulated in the typical 2D in vitro cancer models, where oxygen as well as nutrient exposure is quite uniform. The aim of this study was to investigate the role of a key neutral lipid hydrolase - adipose triglyceride lipase (ATGL) in cancer cells that are exposed to more tumor-like conditions. To that end, we cultured lung cancer cells lacking ATGL as multicellular spheroids in 3D and subjected them to comprehensive proteomics analysis and metabolic phenotyping. Proteomics data are available via ProteomeXchange with identifier PXD021105.As a result, we report that loss of ATGL enhanced growth of spheroids and facilitated their adaptation to hypoxia, by increasing the influx of glucose and endorsing a pro-Warburg effect. This was followed by changes in lipid metabolism and an increase in protein production. Interestingly, the observed phenotype was also recapitulated in an even more "in vivo like" setup, when cancer spheroids were grown on chick chorioallantoic membrane (CAM), but not when cells were cultured as a 2D monolayer. In addition, we demonstrate that according to the publicly available cancer databases, an inverse relation between ATGL expression and higher glucose dependence can be observed. In conclusion, we provide indications that ATGL is involved in regulation of glucose metabolism of cancer cells when grown in 3D (mimicking solid tumors), and as such could be an important factor of the treatment outcome for some cancer types. Lastly, we also ratify the need for alternative cell culture models, as the majority of phenotypes observed in 3D and spheroids grown on CAM were not observed in 2D cell culture.

DOI: https://doi.org/10.1016/j.mcpro.2021.100095

Cancer Res. 2021 May 18. pii: canres.3626.2020. [Epub ahead of print]

Nedd9 restrains autophagy to limit growth of early stage non-small cell lung cancer.

Alexander Y Deneka, Meghan C Kopp, Anna S Nikonova, Anna V Gaponova, Anna A Kiseleva, Harvey H Hensley, Douglas B Flieder, Ilya G Serebriiskii, Erica A Golemis.

Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at <17%, it is critical to identify factors that regulate NSCLC disease prognosis. NSCLC is commonly driven by mutations in KRAS and TP53, with activation of additional kinases such as SRC promoting tumor invasion. In this study, we investigated the role of NEDD9, a SRC activator and scaffolding protein, in NSCLC tumorigenesis. In an inducible model of NSCLC dependent on Kras mutation and Trp53 loss (KP mice), deletion of Nedd9 (KPN mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of KP and KPN tumors into the lungs of Nedd9-wildtype and -null mice indicated the effect of Nedd9 loss was cell-autonomous. Tumors in KPN mice displayed reduced activation of SRC and AKT, indicating that activation of these pathways did not mediate enhanced growth of KPN tumors. NSCLC tumor growth has been shown to require active autophagy, a process dependent on activation of the kinases LKB1 and AMPK. KPN tumors contained high levels of active LKB1 and AMPK and increased autophagy compared to KP tumors. Treatment with the autophagy inhibitor chloroquine completely eliminated the growth advantage of KPN tumors. These data for the first time identify NEDD9 as a negative regulator of LKB1/AMPK-dependent autophagy during early NSCLC tumor growth.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-3626

Am J Transl Res. 2021 ;13(4): 2296-2307

Peroxisome proliferator-activated receptor γ improves pemetrexed therapeutic efficacy in non-squamous non-small cell lung cancer.

Tianxing Hang, Li Yang, Xiujuan Zhang, Jing Li, Feng Long, Ning Zhu, Ying Li, Jingwen Xia, Youzhi Zhang, Peng Zhang, Yuanyuan Zhang, Xiaomin Wei, Shengqing Li.

OBJECTIVE: The folic acid analog pemetrexed (PMX) is recommended for the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, the mechanisms underlying PMX cytotoxicity in NSCLC remain to be fully explored.
METHODS: PMX effect was evaluated in a urethane-induced lung adenocarcinoma mouse model. The interaction between PMX and intracellular proteins, particularly peroxisome proliferator-activated receptor γ (PPARγ), was investigated. The role of PPARγ in mediating pemetrexed cytotoxicity was investigated using NSCLC cell lines, mouse models and clinical specimens.
RESULTS: This study found that PPARγ expression was correlated with prolonged progression-free survival in NSCLC patients. PPARγ downregulated hypoxanthine-guanine phosphoribosyl transferase (HGPRT), a key enzyme for nucleotide salvage synthesis, thereby sensitizing cells to PMX inhibition on nucleotide de novo synthesis. PMX was also a candidate partial agonist of PPARγ, and PMX-activated PPARγ bound to NF-κB and transcriptionally suppressed the NF-κB target gene, c-Myc. PMX inhibited tumor growth by activating PPARγ in a urethane-induced lung cancer model characterized by elevated NF-κB activity.
CONCLUSION: PPARγ improves pemetrexed therapeutic efficacy in non-squamous NSCLC. The cytotoxicity effect of PMX can be synergized by activating PPARγ and thereby inhibiting NF-κB pathway.

Keywords: NF-κB; Peroxisome proliferator-activated receptor γ; hypoxanthine-guanine phosphoribosyl transferase; non-squamous non-small cell lung cancer; pemetrexed

Front Oncol. 2021 ;11 670313

Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer.

Likui Fang, Wuchen Zhao, Bo Ye, Da Chen.

Brain metastases remain a critical issue in the management of non-small cell lung cancer (NSCLC) because of the high frequency and poor prognosis, with survival rates often measured in just months. The local treatment approach remains the current standard of care, but management of multiple asymptomatic brain metastases always involves systemic therapy. Given that anti-angiogenic agents and immune checkpoint inhibitors (ICIs) both target the tumor microenvironment (TME), this combination therapy has become a promising strategy in clinical practice. Increasing number of preclinical and clinical studies have shown remarkable anti-tumor activity of the combination therapy, but the efficacy in brain metastases is unclear due to the strict selection criteria adopted in most clinical trials. This review briefly summarizes the potential synergistic anti-tumor effect and clinical development of the combination of anti-angiogenic agents and ICIs in NSCLC brain metastases, and discusses the existing challenges and problems.

Keywords: anti-angiogenesis; brain metastases; combination therapy; immune checkpoint inhibitors; non-small cell lung cancer

DOI: https://doi.org/10.3389/fonc.2021.670313

Semin Nucl Med. 2021 May 11. pii: S0001-2998(21)00018-0. [Epub ahead of print]

"PET/CT Variants and Pitfalls in Lung Cancer and Mesothelioma".

Egesta Lopci, Carsten Kobe, Gopinath Gnanasegaran, Judit A Adam, Lioe-Fee de Geus-Oei.

2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG-PET/CT represents the metabolic imaging of choice in various cancer types. Used either at diagnosis or during treatment response assessment, the modality allows for a more accurate definition of tumor extent compared to morphological imaging and is able to predict the therapeutic benefit earlier in time. Due to the aspecific uptake property of [18F]FDG there is an overlap of its distribution in normal and pathological conditions, which can make the interpretation of the imaging challenging. Lung and pleural neoplasia are no exception to this, thus acknowledging of possible pitfalls and artifacts are mandatory for image interpretation. While most pitfalls and artifacts are common for all indications with metabolic imaging with [18F]FDG-PET/CT, there are specific variants and pitfalls in lung cancer and malignant pleural mesothelioma. The aim of the present article is to shed light on the most frequent and relevant variants and pitfalls in [18F]FDG-PET/CT imaging in lung cancer and malignant pleural mesothelioma.

DOI: https://doi.org/10.1053/j.semnuclmed.2021.04.002

J Clin Invest. 2021 May 17. pii: 149495. [Epub ahead of print]131(10):

Lung neutrophils on a paleo diet: lean, mean inflammatory machines.

Ian M Cartwright, Sean P Colgan.

Sites of acute inflammation become austere environments for the procurement of energy. The combination of oxygen depletion (hypoxia) and decreased glucose availability requires surprising metabolic adaptability. In this issue of the JCI, Watts et al. examined the metabolic adaptability of murine neutrophils to the setting of acute pulmonary inflammation elicited by exposure to nebulized endotoxin. While neutrophils are generally considered a primarily glycolytic cell type, Watts et al. used a combination of labeled amino acids and high-resolution proteomics to reveal that the harsh environment of the inflammatory lesion drives neutrophils toward de novo protein synthesis and extracellular protein scavenging as a primary fuel. This study provides compelling evidence that tissue neutrophils scavenge extracellular proteins to fuel carbon metabolism, which aids in de novo protein synthesis and the promotion of an inflammatory phenotype. These observations reveal the surprisingly creative extent to which cells and tissues might adapt to energy-deficient inflammatory environments.

DOI: https://doi.org/10.1172/JCI149495