c-MET receptor tyrosine kinase (RTK) activation caused increased membrane dynamics, increased endocytic uptake and the activation and turnover of integrin β1 adhesion receptor ( 13). The Ser/Thr kinase MAP4K4 is overexpressed in MB and contributes to the pro-invasive phenotype of MB cells downstream of HGF-cellular mesenchymal–epithelial transition factor (c-MET) stimulation ( 13, 14). Thus, novel therapeutic options with phenotype-specific anti-tumor activity are needed to replace or complement current treatments and reduce therapy-associated side effects. These anti-cancer therapies can have a devastating impact on the developing brain of the patients and can cause severe long-term side effects such as cognitive or mobility impairments ( 12). Despite this molecular understanding of MB, the current standard therapy still consists of surgical resection of the tumor and craniospinal irradiation followed by chemotherapy ( 11). Several omics studies described the genomic heterogeneity in MB, which is now classified into four subgroups with 12 subtypes in total ( 9, 10). Medulloblastoma (MB) is a malignant embryonal neuroepithelial tumor of the cerebellum with a high propensity to disseminate and metastasize within the central nervous system ( 8). De-regulation of physiological trafficking in tumor cells may thus contribute to cell transformation ( 5), and especially altered endocytic activity can broadly impact tumor cell growth, invasion and metastasis, and viability ( 6, 7).
Moreover, endocytosis and the sequential intracellular vesicular trafficking control adhesion turnover, signal transduction, consequently influencing the duration of mitogenic or motile phenotypes. Membrane trafficking and cytoskeleton reorganization are thus key processes that position chemical and mechanical sensors and enable the uptake of nutrients or extrusion of signal transmitters, thereby determining the cellular response to complex environments. The PM-associated proteome of a cell is dynamically controlled through membrane turnover via endocytic uptake and exocytic fusion ( 3, 4), which involves the dynamic reorganization of the cortical cytoskeleton. The diversity of proteins associated with the PM and their differential expression, localization, or regulation under pathological conditions such as cancer not only define the condition-specific biomarker landscape ( 2), but also constitutes a druggable repertoire of therapeutic targets to interfere with the oncogenic phenotype. Besides these transmembrane proteins, numerous proteins are associated with the PM either directly through lipid anchors, or indirectly by binding to transmembrane proteins. The PM-associated proteome primarily consists of receptors, cell adhesion molecules, enzymes and ion channels ( 1), and their expression defines the strength and duration of signal transmission and how the cell interacts with its environment. The net outcome of the functions of PM-associated proteins affects the cellular phenotype and the composition and biophysical structure of the extracellular microenvironment.
This physical barrier regulates the transfer of chemical and mechanical information between extracellular and intracellular spaces. The plasma membrane (PM)-associated proteome is a dynamic interface of mammalian cells, which orchestrates interactions with the extracellular environment and transmits extracellular cues. These data thus describe a novel function of MAP4K4 in the control of the PM-associated proteome of tumor cells and identified two downstream effector mechanisms controlling proliferation and invasiveness of MB cells. The decreased surface expression of CD155 or of the fast-endophilin–mediated endocytosis effector endophilin-A1 reduces growth and invasiveness of MB tumor cells in the tissue context. The depletion of MAP4K4, a pro-migratory effector kinase downstream of c-MET, leads to a specific decrease of the adhesion and immunomodulatory receptor CD155 and of components of the fast-endophilin–mediated endocytosis (FEME) machinery in the PM-associated proteome of HGF-activated MB cells. Using a spatial proteomics approach, we observed that hepatocyte growth factor (HGF)-induced activation of the receptor tyrosine kinase c-MET in MB cells changes the abundance of transmembrane and membrane-associated proteins. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) tumor cells and how it adapts in response to growth factor cues is poorly understood. The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell–cell and cell–matrix interactions and the response to environmental cues.
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