bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019‒08‒11
two papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. J Thorac Oncol. 2019 Aug 06. pii: S1556-0864(19)30650-1. [Epub ahead of print]
    Yendamuri S, Barbi J, Pabla S, Petrucci C, Punnanitinont A, Nesline M, Glenn ST, Depietro P, Papanicalou-Sengos A, Morrison C, Dy GK, Elkin PL.
      INTRODUCTION: Metformin, a common medication used in the treatment of Diabetes Mellitus is known to have anti-cancer effects. We hypothesized that the salutary effect of metformin on the survival of patients with stage I NSCLC is influenced by body mass index (BMI).METHODS: Patients undergoing lobectomy for stage I NSCLC without neoadjuvant therapy were included. Univariate and multivariate survival analyses to examine the association between metformin use and overall, disease specific and recurrence free survival (OS, DSS and RFS respectively) were performed, stratified by BMI (>25 and <25). Expression of immune checkpoints in patients on metformin and not was performed in a separate cohort of 205 patients with advanced disease.
    RESULTS: 434 stage I patients (including 74 metformin users) were deemed eligible for analysis. Univariate and multivariate analysis revealed an association between metformin use and OS (HR=0.52; P=0.04) as well as DSS (HR=0.21; P=0.04) but not RFS (HR=0.67; P=0.33) in high-BMI patients only. In a separate cohort of 205 tumors of all stages (including 35 metformin users), downregulation of immune checkpoint gene expression (PDCD1, CTLA4, BTLA, CD27, LAG3 and ICOS) in metformin users was seen only in high-BMI patients, with upregulation of these genes seen in low-BMI patients with metformin use.
    CONCLUSIONS: Metformin use may be associated with better OS and DSS only in high-BMI patients. This hypothesis is supported by gene expression data of immune checkpoint genes in metformin users using a separate cohort of advanced stage tumors. Further studies examining the interaction of BMI with metformin in NSCLC are worthwhile.
    Keywords:  Diabetes; Lung cancer; Metformin; survival
  2. Nat Commun. 2019 Aug 08. 10(1): 3578
    Stewart PA, Welsh EA, Slebos RJC, Fang B, Izumi V, Chambers M, Zhang G, Cen L, Pettersson F, Zhang Y, Chen Z, Cheng CH, Thapa R, Thompson Z, Fellows KM, Francis JM, Saller JJ, Mesa T, Zhang C, Yoder S, DeNicola GM, Beg AA, Boyle TA, Teer JK, Ann Chen Y, Koomen JM, Eschrich SA, Haura EB.
      How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1. Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities (TP63, PSAT1, and TFRC) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.