SUMMARY Unresectable glioblastoma (GBM) cells in the invading tumor edge can act as seeds for recurrence. The molecular and phenotypic properties of these cells remain elusive. Here, we report that the invading edge and tumor core have two distinct types of glioma stem-like cells (GSCs) that resemble proneural (PN) and mesenchymal (MES) subtypes, respectively. Upon exposure to ionizing radiation (IR), GSCs, initially enriched for a CD133 + PN signature, transition to a CD109 + MES subtype in a C/EBP-β-dependent manner. Our gene expression analysis of paired cohorts of patients with primary and recurrent GBMs identified a CD133-to-CD109 shift in tumors with an MES recurrence. Patient-derived CD133 − /CD109 + cells are highly enriched with clonogenic, tumor-initiating, and radiation-resistant properties, and silencing CD109 significantly inhibits these phenotypes. We also report a conserved regulation of YAP/TAZ pathways by CD109 that could be a therapeutic target in GBM.

SummaryATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.

The (parameterized) FEEDBACK VERTEX SET problem on directed graphs (i.e., the DFVS problem) is defined as follows: given a directed graph G and a parameter k, either construct a feedback vertex set of at most k vertices in G or report that no such a set exists. It has been a well-known open problem in parameterized computation and complexity whether the DFVS problem is fixed-parameter tractable, that is, whether the problem can be solved in time f (k)n O(1) for some function f . In this article, we develop new algorithmic techniques that result in an algorithm with running time 4 k k!n O(1) for the DFVS problem. Therefore, we resolve this open problem.

The (parameterized) feedback vertex set problem on directed graphs, which we refer to as the dfvs problem, is defined as follows: given a directed graph G and a parameter k, either construct a feedback vertex set of at most k vertices in G or report that no such set exists. Whether or not the dfvs problem is fixed-parameter tractable has been a well-known open problem in parameterized computation and complexity, i.e., whether the problem can be solved in time f (k)n O(1) for some function f . In this paper we develop new algorithmic techniques that result in an algorithm with running time 4 k k!n O(1) for the dfvs problem, thus showing that this problem is fixed-parameter tractable.

Two hallmarks of glioblastoma multiforme, the most common malignant brain cancer in humans, are aggressive growth and the ability of single glioma cells to disperse throughout the brain. These characteristics render tumors resistant to current therapies and account for the poor prognosis of patients. Although it is known that oncogenic signaling caused by overexpression of genes such as PDGFRA is responsible for robust glioma growth and cell infiltration, the mechanisms underlying glioblastoma malignancy remain largely elusive. Here, we report that PDGFRα signaling in glioblastomas leads to Src-dependent phosphorylation of the guanine nucleotide exchange factor Dock180 at tyrosine 1811 (Dock180 Y1811 ) that results in activation of the GTPase Rac1 and subsequent cell growth and invasion. In human glioma cells, knockdown of Dock180 and reversion with an RNAi-resistant Dock180 Y1811F abrogated, whereas an RNAi-resistant Dock180 WT rescued, PDGFRα-promoted glioma growth, survival, and invasion. Phosphorylation of Dock180 Y1811 enhanced its association with CrkII and p130 Cas , causing activation of Rac1 and consequent cell motility. Dock180 also associated with PDGFRα to promote cell migration. Finally, phosphorylated Dock180 Y1811 was detected in clinical samples of gliomas and various types of human cancers, and coexpression of phosphorylated Dock180 Y1811 , phosphorylated Src Y418 , and PDGFRα was predictive of extremely poor prognosis of patients with gliomas. Taken together, our findings provide insight into PDGFRα-stimulated gliomagenesis and suggest that phosphorylated Dock180 Y1811 contributes to activation of Rac1 in human cancers with PDGFRA amplification.