bims-meluca 2019-09-01 papers

Mol Oncol. 2019 Aug 28.

Metabolomics, transcriptomic and genetic-integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non-small cell lung cancer.

Long T Hoang, Clara Domingo-Sabugo, Elizabeth S Starren, Saffron A G Willis-Owen, Deborah J Morris-Rosendahl, Andrew G Nicholson, William O C M Cookson, Miriam F Moffatt.

Lung cancer is the leading cause of cancer-related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non-small cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5-year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesised that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate (ADP) in promoting cancer metastasis through platelet activation and angiogenesis suggests this metabolite could be a potential therapeutic target.

Keywords: ADP; Genetics; Haemostasis; Metabolomic; NSCLC; Platelet Activation; Transcriptomics

DOI: https://doi.org/10.1002/1878-0261.12568

Lung Cancer. 2019 Aug 09. pii: S0169-5002(19)30578-1. [Epub ahead of print]136 57-64

Correlation between maximum standardized uptake values on FDG-PET and microenvironmental factors in patients with clinical stage IA radiologic pure-solid lung adenocarcinoma.

Tomohiro Ichikawa, Keiju Aokage, Tomohiro Miyoshi, Kenta Tane, Kenji Suzuki, Hideki Makinoshima, Masahiro Tsuboi, Genichiro Ishii.

OBJECTIVES: The purpose of this study was to investigate whether fluorodeoxyglucose (FDG) accumulation is associated with the expression of microenvironmental factors in radiological pure-solid lung adenocarcinoma.
METHODS: We selected 50 cases involving patients with clinical stage IA radiological pure-solid lung adenocarcinoma who were examined with 18 F-FDG positron emission tomography (18 F-FDG PET) prior to surgery and whose FDG-PET maximal standardized uptake values (SUVmax) were calculated. Tumor specimens were analyzed by immunohistochemistry (IHC) for phosphorylated AKT (pAKT), glucose transporter type 1 (GLUT-1), carbonic anhydrase IX (CA IX), podoplanin-positive cancer associated fibroblasts (PDPN + CAFs), and CD204-positive tumor-associated macrophages (CD204+ TAMs). We compared the clinicopathological characteristics and the immunophenotypes between two groups with high and low SUVmax.
RESULTS: A multivariate analysis revealed that SUVmax was an independently significant prognostic factor (P = .03). The 5-year overall survival (OS) and recurrence free survival (RFS) rates of the SUV max high and low groups were 68.0% versus 100% ((P = .002; OS) 54.3% versus 90.8% (P < .001; RFS)), respectively. Vascular invasion, pleural invasion, and the prevalence of solid predominant subtype tumors were more frequent in the SUVmax high group. Additionally, the expression levels of GLUT-1 and pAKT in cancer cells were significantly higher in this group (P < .001, and P < .001 respectively). Furthermore, the numbers of the tumor-promoting stromal cells, i.e., PDPN + CAFs and CD204+ TAMs, were also significantly higher in the SUVmax high group (P = .001, and P < .001 respectively).
CONCLUSION: Our results indicated that a close association exists between the SUVmax and expressions of not only metabolism associated markers in cancer cells but also of tumor promoting markers in stromal cells among patients with clinical stage IA adenocarcinoma with radiologically pure-solid nodules.

Keywords: 18F-FDG PET; Lung cancer; Tumor microenvironment

DOI: https://doi.org/10.1016/j.lungcan.2019.08.003

Lung Cancer. 2019 Sep;pii: S0169-5002(19)30529-X. [Epub ahead of print]135 217-227

Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC.

Sarah-Louise Ryan, Sam Beard, Martin P Barr, Kazou Umezawa, Susan Heavey, Peter Godwin, Steven G Gray, David Cormican, Stephen P Finn, Kathy A Gately, Anthony M Davies, Erik W Thompson, Derek J Richard, Kenneth J O'Byrne, Mark N Adams, Anne-Marie Baird.

OBJECTIVES: The majority of patients with non-small cell lung cancer (NSCLC) present with advanced stage disease, at which time chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with platinum-based regimens will eventually develop resistance, with others presenting with intrinsic resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project was to determine the role of inflammatory mediators in cisplatin-resistance in NSCLC.
MATERIALS AND METHODS: Inflammatory mediator, NF-κB, and its associated pathways were investigated in an isogenic model of cisplatin-resistant NSCLC using age-matched parental (PT) and corresponding cisplatin-resistant (CisR) sublines. Pathways were assessed using mass spectrometry, western blot analysis and qRT-PCR. The cisplatin sensitizing potential of an NF-κB small molecule inhibitor, DHMEQ, was also assessed by means of viability assays and western blot analysis.
RESULTS: Proteomic analysis identified dysregulated NF-κB responsive targets in CisR cells when compared to PT cells, with increased NF-κB expression identified in four out of the five NSCLC sub-types examined (CisR versus PT). DHMEQ treatment resulted in reduced NF-κB expression in the presence of cisplatin, and re-sensitized CisR cells to the cytotoxic effects of the drug.
CONCLUSION: This study identified NF-ĸB as a potential therapeutic target in cisplatin-resistant NSCLC. Furthermore, inhibition of NF-ĸB using DHMEQ re-sensitized chemo-resistant cells to cisplatin treatment.

Keywords: Chemotherapy; Cisplatin; DHMEQ; NF-κB; Non-small cell lung cancer; Resistance

DOI: https://doi.org/10.1016/j.lungcan.2019.07.006

Mol Cells. 2019 Aug 31. 42(8): 604-616

Phosphoserine Phosphatase Promotes Lung Cancer Progression through the Dephosphorylation of IRS-1 and a Noncanonical L-Serine-Independent Pathway.

Seong-Min Park, Eun-Hye Seo, Dong-Hyuck Bae, Sung Soo Kim, Jina Kim, Weiwei Lin, Kyung-Hee Kim, Jong Bae Park, Yong Sung Kim, Jinlong Yin, Seon-Young Kim.

Phosphoserine phosphatase (PSPH) is one of the key enzymes of the L-serine synthesis pathway. PSPH is reported to affect the progression and survival of several cancers in an L-serine synthesis-independent manner, but the mechanism remains elusive. We demonstrate that PSPH promotes lung cancer progression through a noncanonical L-serine-independent pathway. PSPH was significantly associated with the prognosis of lung cancer patients and regulated the invasion and colony formation of lung cancer cells. Interestingly, L-serine had no effect on the altered invasion and colony formation by PSPH. Upon measuring the phosphatase activity of PSPH on a serine-phosphorylated peptide, we found that PSPH dephosphorylated phospho-serine in peptide sequences. To identify the target proteins of PSPH, we analyzed the protein phosphorylation profile and the PSPH-interacting protein profile using proteomic analyses and found one putative target protein, IRS-1. Immunoprecipitation and immunoblot assays validated a specific interaction between PSPH and IRS1 and the dephosphorylation of phospho-IRS-1 by PSPH in lung cancer cells. We suggest that the specific interaction and dephosphorylation activity of PSPH have novel therapeutic potential for lung cancer treatment, while the metabolic activity of PSPH, as a therapeutic target, is controversial.

Keywords: IRS-1; L-serine independent pathway; lung cancer; phosphoserine phosphatase

DOI: https://doi.org/10.14348/molcells.2019.0160

Sci Rep. 2019 Aug 27. 9(1): 12437

PIDD interaction with KEAP1 as a new mutation-independent mechanism to promote NRF2 stabilization and chemoresistance in NSCLC.

Lili Ji, Rui Zhang, Jie Chen, Qun Xue, Nadeem Moghal, Ming-Sound Tsao.

Chemotherapy resistance is a major problem in non-small cell lung cancer (NSCLC) treatment. A major mechanism of chemoresistance involves stabilization of the NRF2 transcription factor. NRF2 levels are normally tightly regulated through interaction with KEAP1, an adaptor that targets NRF2 to the CUL3 E3 ubiquitin ligase for proteolysis. In NSCLC, aberrant NRF2 stabilization is best understood through mutations in NRF2, KEAP1, or CUL3 that disrupt their interaction. Biochemical studies, however, have revealed that NRF2 can also be stabilized through expression of KEAP1-interacting proteins that competitively sequester KEAP1 away from NRF2. Here, we have identified PIDD, as a novel KEAP1-interactor in NSCLC that regulates NRF2. We show that this interaction allows PIDD to reduce NRF2 ubiquitination and increase its stability. We also demonstrate that PIDD promotes chemoresistance in NSCLC cells both in vitro and in vivo, and that this effect is dependent on NRF2. Finally, we report that NRF2 protein expression in a NSCLC cohort exceeds the typical incidence of combined NRF2, KEAP1, and CUL3 mutations, and that NRF2 expression in this cohort is correlated with PIDD levels. Our data identify PIDD as a new NRF2 regulator, and suggest that variations in PIDD levels contribute to differential chemosensitivities among NSCLC patients.

DOI: https://doi.org/10.1038/s41598-019-48763-4