bims-meluca 2019-10-27 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–10–27
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Inhibition of Non-Small Cell Lung Cancer Cells by Oxy210, an Oxysterol-Derivative that Antagonizes TGFβ and Hedgehog Signaling.
LKB1 deficiency renders non-small-cell lung cancer cells sensitive to ERK inhibitors.: ERK inhibitors in LKB1 mutated NSCLC.
Non-invasive exploration of metabolic profile of lung cancer with Magnetic Resonance Spectroscopy and Mass Spectrometry.
Expression of DR5 and c‑FLIP proteins as novel prognostic biomarkers for non‑small cell lung cancer patients treated with surgical resection and chemotherapy.
YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.
The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma.
Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition.

Cells. 2019 Oct 22. pii: E1297. [Epub ahead of print]8(10):

Inhibition of Non-Small Cell Lung Cancer Cells by Oxy210, an Oxysterol-Derivative that Antagonizes TGFβ and Hedgehog Signaling.

Frank Stappenbeck, Feng Wang, Liu-Ya Tang, Ying E Zhang, Farhad Parhami.

  Non-Small Cell Lung Cancer (NSCLC) is a common malignancy and leading cause of death by cancer. Metastasis and drug resistance are serious clinical problems encountered in NSCLC therapy. Aberrant activation of the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signal transduction cascades often associate with poor prognosis and aggressive disease progression in NSCLC, as these signals can drive cell proliferation, angiogenesis, metastasis, immune evasion and emergence of drug resistance. Therefore, simultaneous inhibition of TGFβ and Hh signaling, by a single agent, or in combination with other drugs, could yield therapeutic benefits in NSCLC and other cancers. In the current study, we report on the biological and pharmacological evaluation of Oxy210, an oxysterol-based dual inhibitor of TGFβ and Hh signaling. In NSCLC cells, Oxy210 inhibits proliferation, epithelial-mesenchymal transition (EMT) and invasive activity. Combining Oxy210 with Carboplatin (CP) increases the anti-proliferative response to CP and inhibits TGFβ-induced resistance to CP in A549 NSCLC cells. In addition, Oxy210 displays encouraging drug-like properties, including chemical scalability, metabolic stability and oral bioavailability in mice. Unlike other known inhibitors, Oxy210 antagonizes TGFβ and Hh signaling independently of TGFβ receptor kinase inhibition and downstream of Smoothened, respectively.

Keywords:  TGFβ signaling; drug resistance; hedgehog signaling; metastasis; oxysterols

DOI:  https://doi.org/10.3390/cells8101297
J Thorac Oncol. 2019 Oct 18. pii: S1556-0864(19)33568-3. [Epub ahead of print]

LKB1 deficiency renders non-small-cell lung cancer cells sensitive to ERK inhibitors.: ERK inhibitors in LKB1 mutated NSCLC.

Elisa Caiola, Alice Iezzi, Michele Tomanelli, Elisa Bonaldi, Arianna Scagliotti, Marika Colombo, Federica Guffanti, Edoardo Micotti, Marina Chiara Garassino, Lucia Minoli, Eugenio Scanziani, Massimo Broggini, Mirko Marabese.

   BACKGROUND: Liver kinase B1 (LKB1/STK11) is one of the most mutated genes in non-small-cell lung cancer (NSCLC) accounting for about one third of cases and its activity is impaired in about half of KRAS mutated NSCLC. At present, these patients cannot benefit from any specific therapy.
METHODS: Through CRISPR/Cas9 technology, we systematically deleted LKB1 in both wild-type and KRAS-mutated human NSCLC cells. By using these isogenic systems together with genetically engineered mouse models we investigated the cell response to ERK inhibitors both in vitro and in vivo.
RESULTS: In all the systems used here, the loss of LKB1 creates a vulnerability and renders these cells particularly sensitive to ERK inhibitors both in vitro and in vivo. The same cells expressing a wt LKB1 poorly respond to these drugs. At molecular level, ERK inhibitors induced, in the absence of LKB1, a marked inhibition of p90 ribosomal S6 kinase activation, which in turn abolished S6 protein activation, promoting the cytotoxic effect.
CONCLUSIONS: This work shows that ERK inhibitors are effective in LKB1 and LKB1/KRAS mutated tumors, thus offering a therapeutic strategy for this prognostically unfavorable subgroup of patients. Since ERK inhibitors are already in clinical development, our findings could be easily translatable to the clinic. Importantly, the lack of effect in cells expressing wild-type LKB1, predicts that treatment of LKB1 mutated tumors with ERK inhibitors should have a favorable toxicity profile.

Keywords:  ERK inhibitor; LKB1/STK11; NSCLC; SCH772984; ulixertinib

DOI:  https://doi.org/10.1016/j.jtho.2019.10.009
Contemp Clin Trials Commun. 2019 Dec;16 100445

Non-invasive exploration of metabolic profile of lung cancer with Magnetic Resonance Spectroscopy and Mass Spectrometry.

Naseer Ahmed, Biniam Kidane, Le Wang, Gefei Qing, Lawrence Tan, Gordon Buduhan, Sadeesh Srinathan, Michel Aliani.

   Background: Lung cancer is a major cause of global morbidity and mortality. Current low dose CT screening is invasive and its role remains contentious. There are no known biomarkers to monitor treatment response, detect disease recurrence and patient selection for adjuvant treatment after curative surgical resection. Hence there is an urgent need to explore non-conventional and non-invasive tools to develop novel biomarkers to improve the outcome of this lethal cancer.
Methods: This is an ongoing exploratory and translational study involving collection of bio fluids from 50 patients with early stage non-small cell lung cancer before and after surgical resection. The primary objective is to identify cancer specific metabolome in body fluids - sputum, exhaled breath condensate, blood and urine of the patients with early stage non-small cell lung cancer using Magnetic Resonance Spectroscopy and Mass Spectroscopy.
Conclusion: The trajectory of change in metabolic profile of body fluids before and after surgical resection may have potential clinical applications in lung cancer screening, as biomarkers for disease recurrence and exploration of novel targets for therapeutic intervention.

Keywords:  Biomarkers; EBC, exhaled breath condensate; LC, liquid chromatography; LC-QTOF-MS, liquid chromatography quadrupole time-of-flight mass spectrometry; Lung cancer; MRS, magnetic resonance spectroscopy; MS, mass spectrometry; Metabolomics; NMR, nuclear magnetic resonance; NSCLC, non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.conctc.2019.100445
Oncol Rep. 2019 Oct 04.

Expression of DR5 and c‑FLIP proteins as novel prognostic biomarkers for non‑small cell lung cancer patients treated with surgical resection and chemotherapy.

Hongmei Zheng, Yuting Zhang, Yuting Zhan, Sile Liu, Junmi Lu, Qiuyuan Wen, Songqing Fan.

TRAIL‑R2 (DR5), one of the death receptors, can activate the extrinsic apoptosis pathway, while cellular FLICE‑inhibitory protein (c‑FLIP) can inhibit this pathway. Both of them play important roles in the occurrence and development of most tumors. To date, there is no relevant report concerning the relationship between expression of DR5 and c‑FLIP protein and clinicopathological/prognostic implications in patients with non‑small cell lung cancer (NSCLC) treated with surgical resection and chemotherapy. Thus, the aim of the present study was to investigate the potential prognostic significance of DR5 and c‑FLIP in NSCLC patients and their predictive roles in the chemotherapeutic response. In the present study, DR5 and c‑FLIP were detected by immunohistochemistry (IHC) in tissue microarrays of NSCLC. The results showed that the expression levels of DR5 and c‑FLIP were significantly higher in lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC) tissues compared with levels noted in the non‑cancerous control lung tissues (all P<0.05). In addition, DR5 expression was significantly increased in lung ADC (P<0.001), whereas, c‑FLIP was higher in lung SCC (P<0.001) and smoker patients with clinical stage III (P=0.019, P=0.016, respectively). In addition, NSCLC patients with overexpression of DR5 and loss of c‑FLIP expression exhibited a higher overall survival (OS) rate as determined by Kaplan‑Meier analysis (P=0.029, P=0.038, respectively). Multivariate analysis confirmed that high expression of DR5 and loss of c‑FLIP expression were independent favorable prognostic factors for NSCLC patients (P=0.016, P=0.035, respectively). In conclusion, overexpression of DR5 and loss of c‑FLIP expression may serve as novel favorable prognostic biomarkers for NSCLC patients treated with chemotherapy after radical resection and used as predictors for tumor response to chemotherapy drugs.

DOI: https://doi.org/10.3892/or.2019.7355
Nat Commun. 2019 Oct 25. 10(1): 4892

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

Yulin Shi, Songqing Fan, Mengge Wu, Zhixiang Zuo, Xingyang Li, Liping Jiang, Qiushuo Shen, Peifang Xu, Lin Zeng, Yongchun Zhou, Yunchao Huang, Zuozhang Yang, Jumin Zhou, Jing Gao, Hu Zhou, Shuhua Xu, Hongbin Ji, Peng Shi, Dong-Dong Wu, Cuiping Yang, Yongbin Chen.

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.

DOI: https://doi.org/10.1038/s41467-019-12801-6
EMBO Mol Med. 2019 Oct 21. e10849

The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma.

Shengchen Lin, Chongbiao Huang, Jianwei Sun, Oana Bollt, Xiuchao Wang, Eric Martine, Jiaxin Kang, Matthew D Taylor, Bin Fang, Pankaj K Singh, John Koomen, Jihui Hao, Shengyu Yang.

  The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK-mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence.

Keywords:  DGUOK; cancer stem cell; lung cancer; metastasis; mitochondria

DOI:  https://doi.org/10.15252/emmm.201910849
BMC Bioinformatics. 2019 Oct 21. 20(1): 507

Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition.

Emile P Chen, Roy S Song, Xueer Chen.

   BACKGROUND: Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity?
RESULTS: We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differential effects among heterogeneous subpopulation of tumor cells could be governed by varying concentrations of just a few key biomolecules. These biomolecules include activated serine/threonine-specific protein kinases (pRAF), mitogen-activated protein kinase kinase (pMEK), protein kinase B (pAkt), or phosphoinositide-4,5-bisphosphate 3-kinase (pPI3K). Additionally, the ratio of activated extracellular signal-regulated kinases (pERK) or pAkt to its respective total was a key factor in determining the sensitivity of pERK or pAkt to hypoxia.
CONCLUSION: This work offers a mechanistic insight into how hypoxia can affect the efficacy of anti-cancer drug that targets tumor signaling and provides a framework to identify the types of tumor cells that are either sensitive or resistant to anti-cancer therapy.

Keywords:  Hypoxia tumor signaling; Mathematical tumor model; Tumor growth model; Tumor signaling

DOI:  https://doi.org/10.1186/s12859-019-3098-5