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

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.

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

“…This is most likely due to dasatinib inhibition of SRC family kinases, which are necessary for focal adhesion formation and turnover [36] . Similarly, dasatinib treatment of cells invading collagen I gels, a soft matrix triggering mesenchymal, integrin-dependent migration of DAOY cells [40] , caused de-adhesion and cell rounding in other human tumor cells [36] . The process of migration associated with cell rounding and blebbing in response to de-adhesion and repression of pericellular proteolytic activity was referred to as mesenchymal to amoeboid transition (MAT) [41] , [42] .…”

Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion

“…Previous studies have suggested the importance of MAP4K4 in migration. Recently, MAP4K4 expression was shown to be increased in 30% of primary medulloblastoma tumors, particularly in the metastatic SHH β subtype, and was shown to promote the migratory and invasive behavior of medulloblastoma tumor cells 33 . A small interfering RNA screen for modulators of tumor cell motility in an ovarian cancer line identified MAP4K4 as a pro-migratory kinase 32 .…”

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

“…Parallel activation of FGFR and SHH signaling partially phenocopies SMO inhibition by LDE225 and reduces invasion. LDE225 treatment can repress phosphorylation of focal adhesion kinase (FAK) and paxillin [22,23], two molecules critically implicated in integrin-dependent motility and invasiveness in numerous cancers, including MB [24]. SHH signaling promotes epithelial to mesenchymal transition (EMT) and lymph node invasion in bladder cancer [25,26] and hypoxia-induced up-regulation of cancer stem cell genes and EMT in cholangiocarcinoma [27].…”