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In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKCĪ± as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients.
Pubmed ID: 31775562
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Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
View all literature mentionsAn independent, not-for-profit biobanking and biotechnology foundation designed to facilitate new, high quality medical research. The IBBL collects, stores, and analyzes biological samples and associated data, which are then made available to research organizations investigating new treatments for diseases. It houses a biospecimen collection and biorepository that contains high quality tissues and maintains quality control of the specimens and the clinical data associated with the tissue samples, while maintaining biobanking ethical standards. It also provides biorefinery analyses and research services that can make analytes from tissues (e.g. DNA, RNA and protein), maintains technology for high throughput gene sequencing and gene expression, and conducts biospecimen research. An informatics platform maintains the clinical and biospecimens data in a secure fashion for additional analysis. Samples are collected by IBBL personnel from hospitals in a targeted manner. The IBBL collaborates with research and health organizations in North America, Europe and the Middle East, and with the major international biobanking societies.
View all literature mentionsAn Organization portal, Antibody supplier, Service resource,
View all literature mentionsSoftware tool for limiting dilution analysis, with particular attention to needs of stem cell assays. Provides confidence intervals for all LDA data sets, including those with 0% or 100% responses. Other features include test of adequacy of single hit hypothesis, tests for frequency differences between multiple data sets, and ability to take advantage of cases where number of cells in sample is counted exactly.
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