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F. Michor



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    P1.03 - Poster Session with Presenters Present (ID 455)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P1.03-003 - The Warburg Effect: Persistence of Stem Cell Metabolism in Lung Cancer as Failure of Differentiation (ID 4378)

      14:30 - 14:30  |  Author(s): F. Michor

      • Abstract

      Background:
      Two recent observations are relevant to explaining Warburg's observation the cancers constitutively utilize glycolysis in the presence of oxygen sufficient for oxidative phosphorylation. First, the metabolism of stem cells has been shown to be constitutive (‘aerobic’) glycolysis, with differentiation involving a transition to oxidative phosphorylation. Second, the degree of glucose uptake by a cancer has been associated with histologic differentiation. We hypothesized that the high levels of glucose uptake observed in poorly differentiated lung cancers may reflect persistence in cancers of the glycolytic metabolism of stem cells that fail to fully differentiate.

      Methods:
      Tumor glucose uptake was measured by FDG-PET in 859 patients with histologically diverse cancers including NSCLC. We used normal mixture modeling to explore SUV distributions and tested for association between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using microarray data, we performed pathway and transcription factor analyses to compare tumors with high/low glucose uptake.

      Results:
      Well-differentiated NSCLC had low FDG uptake, and moderately/poorly differentiated tumors higher uptake. The distribution of FDG-PET uptake was modal with a low peak at SUV 2-4 and a high peak at SUV 8-11. Figure 1 The cancers in the two peaks were clinically distinct in terms of the risk of nodal metastases and of death. Carbohydrate metabolism-related and pentose/nucleotide synthesis-related genes were elevated in the high SUV clusters, Krebs cycle/glutamine metabolism-related genes were elevated in the low SUV mode samples. Expression of Myc target genes was associated with SUV mode, but Nanog, Sox2, Oct4 and PRC2 where not.



      Conclusion:
      The biological basis for the Warburg effect is persistence of stem cell metabolism in lung cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. Lung cancers cluster along the differentiation pathway into two groups. Our results have implications for determining prognosis, cancer screening and surveillance after resection.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-026 - A Mass Spectrometry Based Stem Cell-Oriented Phylogeny of Intra-Tumoral NSCLC Subclones (ID 4385)

      14:30 - 14:30  |  Author(s): F. Michor

      • Abstract

      Background:
      Sub-clones within a cancer diverge due to ongoing accumulation of mutations. We sought to characterize the intratumor heterogeneity and phylogenetic relationships among different histological patterns present in lung adenocarcinomas based on mass spectrometric analysis of tumor subclones.

      Methods:
      MALDI-TOF mass spectrometry was used to generate proteomics data from different histological regions of 35 resected lung tumors, as well as from 3 basal cell and 3 mesenchymal cell samples. A total of 1985 different histological regions were analyzed from the 35 resected tumors along with the 3 samples each of airway basal cells and mesenchymal stem cells. For each of the 1991 samples, a spectral profile was generated with expression data from 217 peptide mass peaks to allow comparison of the proteomics profiles from the different histological regions from each cancer to the basal and mesenchymal stem cell profiles. Weighted protein co-expression networks were analyzed by using WGCNA package in R. Global and histologic specific networks were generated through using a power adjacency function which defines the similarity between any pairs of proteins The network modules were decided by using average linkage hierarchical clustering and a dynamic tree-cut algorithm. Networks of the different histologies and normal were compared and visualized by heat map methods.

      Results:
      The clinically more aggressive histologies ( micropapillary/solid) clustered with stem cells and away from normal alveolar tissue (Fig 1) and had severe loss in peptide connectivities (Fig 3). Applying t-SNE dimensionality reduction method showed that subclones from one specimen cluster differently from each other suggesting underlying heterogeneity, with more heterogenous tumors being associated with worse prognosis (Fig 2). Figure 1



      Conclusion:
      Construction of a phylogenetic tree of lung ACA subclones oriented to stem cells demonstrated that the degree of disruption of a subclone correlated with the degree of similarity of the subclone to stem cells, and with prognosis.

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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-059 - A Stem-Cell Oriented Phylogeny of Non-Small Cell Lung Cancers (ID 4387)

      14:30 - 14:30  |  Author(s): F. Michor

      • Abstract

      Background:
      The degree of histologic cellular differentiation of a lung cancer has been associated with prognosis but is subjectively assessed. We hypothesized that information about tumor differentiation of individual cancers could be derived objectively from cancer gene expression data, and would allow creation of a cancer phylogenetic framework that would correlate with clinical, histologic and molecular characteristics of the cancers, as well as predict prognosis.

      Methods:
      We utilized mRNA expression data from NSCLC samples to explore the utility of ordering samples by their distance in gene expression from that of stem cells. A differentiation baseline was obtained by including expression data of human embryonic stem cells (hESC) and human mesenchymal stem cells (hMSC) for solid tumors, and of hESC and CD34+ cells for liquid tumors.

      Results:
      We found that the correlation distance (the degree of similarity) between the gene expression profile of a tumor sample and that of stem cells oriented lung cancers in a clinically coherent fashion. Cancers most similar to stem cells in gene expression are in general undifferentiated, larger, more likely to be node positive and more FDG avid on PET imaging. Most importantly,patients with cancers with gene expression patterns most similar to that of stem cells had poorer overall survival. Figure 1



      Conclusion:
      A stem cell oriented phylogeny of lung cancers objectively orients cancers by level of differentiation in a clinically coherent fashion. Lung cancers most similar to stem cells in expression are associated with a poorer prognosis after treatment.