Myosin 10 Regulates Invasion, Mitosis, and Metabolic Signaling in Glioblastoma

Kechappa, Rajappa; Mistriotis, Panagiotis; Wisniewski, Emily; Bhattacharya, Santanu; Kulkarmi, Tanmay; West, Rita; Luu, Amanda; Conlon, Meghan; Heimsath, Ernest G.; Crish, James F.; Picariello, Hannah; Dovas, Athanassios; Zarco, Natanael; Lara-Velazquez, Montserrat; Quiñones‐Hinojosa, Alfredo; Hammer, John A.; Mukhopadhyay, Debrabrata; Cheney, Richard E.; Κωνσταντόπουλος, Κωνσταντίνος; Canoll, Peter; Rosenfeld, Steven S.

doi:10.2139/ssrn.3691241

Cited by 4 publications

(5 citation statements)

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“…Complete loss of Myo10 led to about 50% embryonic lethality ( 29 , 35 ), which limited us to obtain enough number of PyMT/ Myo10 −/− female mice. Given that MYO10 depletion slowed glioma proliferation and prolonged mice survival ( 58 ), we would predict that Myo10 −/− might further delay tumor development driven by PyMT, which will be examined when enough PyMT/ Myo10 −/− female mice could be obtained. Nonetheless, the significant inhibition of PyMT tumor in heterozygous Myo10 +/− mice strongly supports the role of MYO10 in promoting breast tumorigenesis.…”

Section: Resultsmentioning

confidence: 99%

MYO10 drives genomic instability and inflammation in cancer

et al. 2021

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Genomic instability is a hallmark of human cancer; yet the underlying mechanisms remain poorly understood. Here, we report that the cytoplasmic unconventional Myosin X (MYO10) regulates genome stability, through which it mediates inflammation in cancer. MYO10 is an unstable protein that undergoes ubiquitin-conjugating enzyme H7 (UbcH7)/-transducin repeat containing protein 1 (-TrCP1)-dependent degradation. MYO10 is upregulated in both human and mouse tumors and its expression level predisposes tumor progression and response to immune therapy. Overexpressing MYO10 increased genomic instability, elevated the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING)-dependent inflammatory response, and accelerated tumor growth in mice. Conversely, depletion of MYO10 ameliorated genomic instability and reduced the inflammation signaling. Further, inhibiting inflammation or disrupting Myo10 significantly suppressed the growth of both human and mouse breast tumors in mice. Our data suggest that MYO10 promotes tumor progression through inducing genomic instability, which, in turn, creates an immunogenic environment for immune checkpoint blockades.

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Section: Resultsmentioning

confidence: 99%

MYO10 drives genomic instability and inflammation in cancer

et al. 2021

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“…First, Collucio and colleagues [76] reported that depletion of Myo10 in mouse models of melanoma reduces melanoma development and metastasis and extends medial survival time. Similarly, Rosenfeld and colleagues [77] reported that the lifespan of mice with glioblastoma is extended significantly on a Myo10 KO background. Third, Zhang and colleagues [78] reported that the progression of breast cancer tumors in mice is inhibited by Myo10 depletion and accelerated by Myo10 over expression.…”

Section: Discussionmentioning

confidence: 93%

Myosin 10 supports mitotic spindle bipolarity by promoting PCM integrity and supernumerary centrosome clustering

Yim

Pedrosa

et al. 2022

Preprint

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Myosin 10 (Myo10) is a member of the MyTH4/FERM domain family of unconventional, actin-based motor proteins. Studies have implicated Myo10 in supporting cell adhesion via its integrin-binding FERM domain, and spindle positioning and spindle pole integrity via its microtubule-binding MyTH4 domain. Here we characterized Myo10s contribution to mitosis using Myo10 knockout HeLa cells and MEFs isolated from a Myo10 knockout mouse. Most notably, both of these knockout cells exhibit a pronounced increase in the frequency of multipolar spindles. Staining of unsynchronized metaphase cells showed that the primary driver of spindle multipolarity in knockout MEFs and knockout HeLa cells lacking supernumerary centrosomes is PCM fragmentation, which creates y-tubulin-positive, centriole-negative microtubule asters that serve as additional spindle poles. For HeLa cells possessing supernumerary centrosomes, Myo10 depletion further accentuates spindle multipolarity by impairing centrosome clustering. These results argue, therefore, that Myo10 supports spindle bipolarity by maintaining PCM integrity in both normal and cancer cells, and by promoting supernumerary centrosome clustering in cancer cells. Finally, we present evidence that the defect in spindle pole integrity in Myo10 knockout cells is likely due to a defect in pole stability rather than pole maturation, and that Myo10 promotes supernumerary centrosome clustering at least in part by promoting cell adhesion during mitosis.

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“…MYO10 is frequently overexpressed in breast cancer, where its expression correlates with poor prognosis and mutant p53 expression (Arjonen et al, 2014; Cao et al, 2014). MYO10 silencing decreases cancer cell invasion, and metastases of aggressive breast cancer cells in vitro and in vivo (Arjonen et al, 2014), and MYO10 contributes to the invasion of other aggressive cancers, including melanoma and glioblastoma (Kenchappa et al, 2020; Tokuo et al, 2018). In line with these previous studies, we found that targeting MYO10 expression leads to reduced cell migration in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Filopodia-mediated basement membrane assembly at pre-invasive tumor boundaries

Peuhu

Jacquemet

Scheele

et al. 2021

Preprint

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The mechanisms triggering the transition from in situ tumors to invasive carcinomas are poorly understood. The process involves breaching tumor-containing basement membranes (BM) and cancer cell invasion into the tumor stroma. Myosin-X (MYO10) is a filopodia-inducing protein frequently overexpressed in metastatic breast cancer. Here, we investigated the contribution of MYO10 to invasive breast tumor progression. We found that downregulation of MYO10 expression reduces breast cancer cell protrusions and migration in vitro. In addition, it attenuates protrusive activity and cell motility in early-stage breast cancer xenografts, which is in line with MYO10’s established pro-invasive function. However, MYO10 depletion also promoted the local dispersal of increasingly basal-like tumor cells into the tumor stroma in vivo, resembling the transition from in situ to invasive tumors. MYO10-depleted tumors exhibited compromised BM structures, which correlated with increased mRNA expression but the reduced assembly of BM proteins surrounding the xenograft. Furthermore, MYO10-depleted 3D spheroids were defective in extracellular matrix (ECM) assembly around the spheroids, indicating a functional role for MYO10 in ECM deposition. Altogether, our data support a model where tumor cell protrusive activity, induced by MYO10, contributes to anti-invasive ECM organization at the in situ stages of breast cancer but promotes cell motility in advanced invasive breast cancer.

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Myosin 10 Regulates Invasion, Mitosis, and Metabolic Signaling in Glioblastoma

Cited by 4 publications

References 0 publications

MYO10 drives genomic instability and inflammation in cancer

MYO10 drives genomic instability and inflammation in cancer

Myosin 10 supports mitotic spindle bipolarity by promoting PCM integrity and supernumerary centrosome clustering

Filopodia-mediated basement membrane assembly at pre-invasive tumor boundaries

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