Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Abstract

The ability of glioblastoma to disperse through the brain contributes to its lethality, and blocking this behavior has been an appealing therapeutic approach. Although a number of proinvasive signaling pathways are active in glioblastoma, many are redundant, so targeting one can be overcome by activating another. However, these pathways converge on nonredundant components of the cytoskeleton, and we have shown that inhibiting one of these—the myosin II family of cytoskeletal motors—blocks glioblastoma invasion even with simultaneous activation of multiple upstream promigratory pathways. Myosin IIA and IIB are the most prevalent isoforms of myosin II in glioblastoma, and we now show that codeleting these myosins markedly impairs tumorigenesis and significantly prolongs survival in a rodent model of this disease. However, while targeting just myosin IIA also impairs tumor invasion, it surprisingly increases tumor proliferation in a manner that depends on environmental mechanics. On soft surfaces myosin IIA deletion enhances ERK1/2 activity, while on stiff surfaces it enhances the activity of NFκB, not only in glioblastoma but in triple-negative breast carcinoma and normal keratinocytes as well. We conclude myosin IIA suppresses tumorigenesis in at least two ways that are modulated by the mechanics of the tumor and its stroma. Our results also suggest that inhibiting tumor invasion can enhance tumor proliferation and that effective therapy requires targeting cellular components that drive both proliferation and invasion simultaneously.

How the mechanobiome drives cell behavior, viewed through the lens of control theory

“…For example, one might want to pharmacologically target a key component (e.g. a non-muscle myosin II) to treat cancer (Ivkovic et al, 2012;Surcel et al, 2015;Wong et al, 2015;Picariello et al, 2019;Surcel and Robinson, 2019;. However, if the system is shifted one way or the other relative to its setpoint optimum, it would be possible to erroneously shift the system so that the disease scenario is exacerbated instead of corrected or improved.…”

“…Loss of ARID1A or SWI/SNF through genetic lesions may have decreased thresholds for YAP activation, leading to loss of differentiation in tumor cells (Chang et al, 2018). Similarly, the loss of negative regulation of YAP by myosin II allows for activation of pro-growth pathways in cancer cells and tumorigenesis (Picariello et al, 2019).…”

Modeling invasion patterns in the glioblastoma battlefield

“…GB infiltration in the human brain is a complex phenomenon, influenced by different tumor properties and the tumor microenvironment, including brain-resident cells, blood brain barrier, and immune system (5). In particular, GB develops fronts of invasion towards uncontaminated areas of the brain, and GB cells modify their cytoskeleton components (6) to extend protrusions, known as Tumor Microtubes (TMs) (7). TMs mediate GB progression, and they interact with synapses of neighboring neurons (8,9).…”

Patient-derived glioblastoma cells (GBM) exhibit distinct biomechanical profiles associated with altered activity in the cytoskeleton regulatory pathway

“…Briefly, decreased activity of Myosin IIA and IIB in GBM cells, particularly Myosin IIA, resulted in reduced tumor cell invasion in vitro and in a rodent model[43][44][45]. However, decreased Myosin IIA expression also enhanced proliferation in a manner dependent on the mechanical properties of the tissue microenvironment[45]. Our data, obtained using direct comparison of the proteome oftwo representative treatment naïve cell lines, also revealed differential expression of cytoskeletal regulation pathways, including cytoskeletal protein-binding and myosin-binding pathways.…”