Angela M. Krebs

Abstract Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604–18. ©2018 AACR.

Abstract The multizinc finger containing transcription factor ZEB1 plays crucial roles during various aspects of mammalian development and tumorigenesis. Best studied in human tumors, ZEB1 is activating the embryo‐derived program of epithelial‐mesenchymal transition (EMT). The aberrant activation of EMT confers an invasive metastasizing phenotype with acquisition of stem cell properties and resistance to radio‐ and chemotherapy. Although ZEB1 has very important functions in tumor progression, not much is known about its role in physiological contexts and during development and homeostasis. We describe the generation of Zeb1 flox/flox mice carrying a targeted mutation for conditional Zeb1 gene inactivation and show that homozygous Zeb1 ‐depletion in the germline results in a phenotype similar to the conventional Zeb1 knockout.

Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.

The integration of Time-Differenced Carrier Phase (TDCP) with RANdom SAmple Consensus (RANSAC) into a generic RTK/PPK architecture is presented in this work. The traditional pre-filtering and validation stages of RTK/PPK will be assisted with outcomes from a RANSAC/TDCP solution computed at the rover receiver. The proposed architecture has been demonstrated with a PPK solution using measurements recorded with low-cost multi-GNSS receivers that are processed with an open-source, open-interface software receiver package.