LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program

Abstract

The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockdown of LIN28A using lentiviral shRNA in GBM cell lines inhibited their invasion, growth and clonogenicity. Expression of LIN28A in GBM cell lines increased the number and size of orthotopic xenograft tumors. LIN28A expression also enhanced the invasiveness of GBM cells in vitro and in vivo. Increasing LIN28A was associated with down-regulation of tumor suppressing microRNAs let-7b and let-7g and up-regulation of the chromatin modifying protein HMGA2. The increase in tumor cell aggressiveness in vivo and in vitro was accompanied by an upregulation of pro-invasive gene expression, including SNAI1. To further investigate the oncogenic potential of LIN28A, we infected hNSC with lentiviruses encoding LIN28A together with dominant negative R248W-TP53, constitutively active KRAS and hTERT. Resulting subclones proliferated at an increased rate and formed invasive GBM-like tumors in orthotopic xenografts in immunodeficient mice. Similar to LIN28A-transduced GBM neurosphere lines, hNSC-derived tumor cells showed increased expression of HMGA2. Taken together, these data suggest a role for LIN28A in high grade gliomas and illustrate an HMGA2-associated, pro-invasive program that can be activated in GBM by LIN28A-mediated suppression of let-7 microRNAs.

CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity

“…Notably, although we observed cytoplasmic LIN28 expression uniformly (100 %) in C19MC amplified CNS-PNETs, our analyses also revealed cytoplasmic as well as nuclear LIN28 staining in a subset of MBs, ATRTs, EPNs and HGGs but not CPCs. Similar to prior reports of cytoplasmic LIN28 staining in 20–60 % of pediatric and adult gliomas [15] and 64 % of ATRTs [3], we observed strong LIN28 cytoplasmic staining in up to 20–25 % of ATRTs and HGGs analyzed (Supplemental Tables 1, 3), which contrasts with a report of cytoplasmic LIN28 immunostaining exclusively in ETANTRs [11]. The reason underlying these discrepant observations is unclear and may be related to the limitations of tissue microarray analyses to comprehensively capture tumor heterogeneity.…”

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

“…Recently, high levels of both Lin28A and Lin28B were also observed in high-grade gliomas and associated with invasiveness and proliferation (Mao et al, 2013). We also observed that several mesenchymal markers were strongly reduced upon Ezh2 depletion in glioblastoma, whereas epithelial markers were upregulated.…”

Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition

“…Orthotopic injections were performed after anesthesia with ketamine/xylazine, as previously described (25). Coordinates for brainstem injections were −5 from bregma, 1 to right, and 3.5 deep.…”