MACC1 driven alterations in cellular biomechanics facilitate cell motility in glioblastoma

Tim Hohmann,Faramarz Dehghani,Mathias Dahlmann,Ulrike Stein,Urszula Hohmann,Marc R Kolbe,Dennis Kobelt

doi:10.1186/s12964-020-00566-1

Abstract

BackgroundMetastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). Nevertheless, the mechanism underlying the increased migratory capacity in GBM is not comprehensively explored.MethodsWe performed live cell and atomic force microscopy measurements to assess cell migration and mechanical properties of MACC1 overexpressing GBM cells. We quantified MACC1 dependent dynamics of 3D aggregate formation. For mechanistic studies we measured the expression of key adhesion molecules using qRT-PCR, and MACC1 dependent changes in short term adhesion to fibronectin and laminin. We then determined changes in sub-cellular distribution of integrins and actin in dependence of MACC1, but also in microtubule and intermediate filament organization.ResultsMACC1 increased the migratory speed and elastic modulus of GBM cells, but decreased cell-cell adhesion and inhibited the formation of 3D aggregates. These effects were not associated with altered mRNA expression of several key adhesion molecules or altered short-term affinity to laminin and fibronectin. MACC1 did neither change the organization of the microtubule nor intermediate filament cytoskeleton, but resulted in increased amounts of protrusive actin on laminin.ConclusionMACC1 overexpression increases elastic modulus and migration and reduces adhesion of GBM cells thereby impeding 3D aggregate formation. The underlying molecular mechanism is independent on the organization of microtubules, intermediate filaments and several key adhesion molecules, but depends on adhesion to laminin. Thus, targeting re-organization of the cytoskeleton and cell motility via MACC1 may offer a treatment option to impede GBM spreading.2KztNGD5eRtzxX41hNP-QCVideo

Highlights

Metastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM)
MACC1 increases single cell motility and elastic modulus We first evaluated if MACC1 overexpressed in the GBM cell lines U251 and U138 (Fig. 1a)
We observed an increase in mean speed for both U251/MACC1 (v U251/EV = 0.43 μm/min, v U251/MACC1 = 0.51 μm/min) and U138/ MACC1 (v U138/EV = 0.32 μm/min, v U138/MACC1 = 0.71 μm/min) cells, relative to their respective controls (Fig. 1b)

Summary

Introduction

Metastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). The mechanism underlying the increased migratory capacity in GBM is not comprehensively explored. One highly lethal tumor entity is glioblastoma (GBM), with a median survival time of approximately 14 month [3]. The poor prognosis for GBM patients is caused by its resistance to standard therapy. The migratory capabilities of GBM cells pose a major obstacle in therapy, as cells distant from the main tumor mass escape resection and will form new tumors. Metastasis-associated in colon cancer 1 (MACC1) has been shown to be important for signaling through c-Met [10,11,12,13]

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