MAP4K4 controlled integrin β1 activation and c-Met endocytosis are associated with invasive behavior of medulloblastoma cells.

Dimitra Tripolitsioti,Jessica Migliavacca,Karthiga Santhana Kumar,Min Ma,Ashish Sharma,Noriyuki Kijima,Elisabeth J Rushing,Martin Pruschy,Charles Capdeville,Michael D Taylor,Anuja Neve,Scott Mccomb,Martin Baumgartner,Michael A Grotzer

doi:10.18632/oncotarget.25294

Dimitra Tripolitsioti, Jessica Migliavacca + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.25294

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Abstract

Local tissue infiltration of Medulloblastoma (MB) tumor cells precedes metastatic disease but little is still known about intrinsic regulation of migration and invasion in these cells.We found that MAP4K4, a pro-migratory Ser/Thr kinase, is overexpressed in 30% of primary MB tumors and that increased expression is particularly associated with the frequently metastatic SHH β subtype. MAP4K4 is a driver of migration and invasion downstream of c-Met, which is transcriptionally up-regulated in SHH MB. Consistently, depletion of MAP4K4 in MB tumor cells restricts HGF-driven matrix invasion in vitro and brain tissue infiltration ex vivo. We show that these pro-migratory functions of MAP4K4 involve the activation of the integrin β-1 adhesion receptor and are associated with increased endocytic uptake. The consequent enhanced recycling of c-Met caused by MAP4K4 results in the accumulation of activated c-Met in cytosolic vesicles, which is required for sustained signaling and downstream pathway activation.The parallel increase of c-Met and MAP4K4 expression in SHH MB could predict an increased potential of these tumors to infiltrate brain tissue and cause metastatic disease. Molecular targeting of the underlying accelerated endocytosis and receptor recycling could represent a novel approach to block pro-migratory effector functions of MAP4K4 in metastatic cancers.

Highlights

Medulloblastoma (MB), the most common malignant brain tumor in childhood, arises in the cerebellum, locally infiltrates and has the propensity for leptomeningeal spread through the cerebrospinal fluid (CSF)
The majority of high Mitogen activated kinase kinase kinase kinase 4 (MAP4K4) SHH tumors express high levels of the c-Met receptor tyrosine kinase (Figure 1C), which is enriched in all four SHH subtypes (Supplementary Figure 1A)
MAP4K4 expression is increased in MB compared to healthy cerebellum and increased levels can be detected both at the mRNA and the protein levels

Summary

Introduction

Medulloblastoma (MB), the most common malignant brain tumor in childhood, arises in the cerebellum, locally infiltrates and has the propensity for leptomeningeal spread through the cerebrospinal fluid (CSF). MB is molecularly classified into the subgroups WNT (Wingless), SHH (Sonic hedgehog) p53-wild-type and SHH p53-mutant and groups 3 and 4 [1]. Large-scale, genome-wide DNA methylation and gene expression analyses combined with copy number aberrations and clinical features have recently allowed to further refine the four subgroup classification of MB [2] into a total of 12 subtypes [3, 4]. Of particular significance is the finding that SHH β subtype tumors are frequently metastatic, a feature that has so far not been attributed to the SHH subgroup and that is mechanistically not understood [4]. Survival rates across www.oncotarget.com all MB subgroups of approximately 70% can be reached [5]. Metastatic and recurrent MB remains clinically very challenging with high mortality rates

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