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Targeting the Cohesive Cluster Phenotype in Chordoma via ?1 Integrin Increases Ionizing Radiation Efficacy.

ABSTRACT: Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (?H2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an ?6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in ?H2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by ?H2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were ?H2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved ?H2AX response. ?1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype.

SUBMITTER: Harryman WL

PROVIDER: S-EPMC5614733 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy.

Harryman William L WL Gard Jaime M C JMC Pond Kelvin W KW Simpson Skyler J SJ Heppner Lucas H LH Hernandez-Cortes Daniel D Little Andrew S AS Eschbacher Jennifer M JM Cress Anne E AE

Neoplasia (New York, N.Y.) 20170924 11

Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% ...[more]

PMID: 28954241

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Project description:Increased glycolytic activity is a hallmark of cancer initiation and progression and is often observed in non-small cell lung cancer (NSCLC). Pyruvate dehydrogenase (PDH) complex acts as a gatekeeper between glycolysis and oxidative phosphorylation, and activation of PDH is known to inhibit glycolytic activity. As part of a standard therapeutic regimen, patients with NSCLC harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) are treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Independent of good initial response, development of resistance to this therapy is inevitable. In the presented work, we propose that inhibition of glycolysis will add to the therapeutic effects and possibly prevent development of resistance against both EGFR TKIs and ionizing radiation in NSCLC. Analysis of transcriptome data from two independent NSCLC patient cohorts identified increased expression of pyruvate dehydrogenase kinase 1 (PDHK1) as well as upregulated expression of genes involved in glucose metabolism in tumors compared to normal tissue. We established in vitro models of development of resistance to EGFR TKIs to study metabolism and determine if targeting PDHK would prevent development of resistance to EGFR TKIs in NSCLC cells. The PDHK1 inhibitor dichloroacetate (DCA) in combination with EGFR TKIs and/or ionizing radiation was shown to increase the therapeutic effect in our NSCLC cell models. This mechanism was associated with redirected metabolism towards pyruvate oxidation and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Using DCA, the intracellular pool of pyruvate available for lactic fermentation becomes limited. Consequently, pyruvate is redirected to the mitochondria, and reinforces mitochondrial activity. Addition of DCA to cell culture deacidifies the extracellular microenvironment as less lactate is produced and excreted. In our study, we find that this redirection of metabolism adds to the therapeutic effect of EGFR TKI and ionizing radiation in NSCLC.

Dataset Information

Targeting the Cohesive Cluster Phenotype in Chordoma via ?1 Integrin Increases Ionizing Radiation Efficacy.

Publications

Targeting the Cohesive Cluster Phenotype in Chordoma via β1 Integrin Increases Ionizing Radiation Efficacy.

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