Dataset Information

Glioblastoma-derived migrasomes promote migration and invasion by releasing PAK4 and LAMA4

ABSTRACT: Almost all high-grade gliomas, particularly glioblastoma (GBM), are highly migratory and aggressive. Migrasomes are organelles produced by highly migratory cells capable of mediating intercellular communication. Thus, GBM cells may produce migrasomes during migration. However, it remains unclear whether migrasomes can influence GBM migration and invasion. In this study, we observed the presence and formation of migrasomes in GBM cells. We found that expression levels of key migrasome formation factor, tetraspanin 4 (TSPAN4), correlated positively with pathological grade and poor prognosis of GBM based on the databases and clinical samples analysis. Subsequently, we knocked down TSPAN4 and found that GBM migration and invasion were significantly inhibited due to the reduced formation of migrasomes. We further confirmed that migrasomes are enriched in extracellular matrix (ECM)-related proteins such as p21-activating kinase 4 (PAK4) and laminin alpha 4 (LAMA4). Our experimental results suggest that migrasomes promote GBM migration by releasing such proteins into the extracellular space. Overall, we identified migrasomes in GBM and the molecular mechanisms by which they regulate them, providing potential targets for treating GBM.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ligang Chen

PROVIDER: PXD057558 | iProX | Tue Nov 05 00:00:00 GMT 2024

REPOSITORIES: iProX

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Glioblastoma-derived migrasomes promote migration and invasion by releasing PAK4 and LAMA4.

Huang Zhe Z Wang Ming M Chen Yitian Y Tang Hua H Tang Kuo K Zhao Mingkuan M Yang Wei W Zhou Zhengjun Z Tian Junjie J Xiang Wei W Li Shenjie S Luo Qinglian Q Liu Luotong L Zhao Yanru Y Li Tao T Zhou Jie J Chen Ligang L

Communications biology 20250120 1

Almost all high-grade gliomas, particularly glioblastoma (GBM), are highly migratory and aggressive. Migrasomes are organelles produced by highly migratory cells capable of mediating intercellular communication. Thus, GBM cells may produce migrasomes during migration. However, it remains unclear whether migrasomes can influence GBM migration and invasion. In this study, we observed the presence and formation of migrasomes in GBM cells. We found that expression levels of key migrasome formation f ...[more]

PMID: 39833606

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Project description:Treating recurrent GBM is a clinical challenge due to its highly resistant and aggressive nature. In order to develop new therapeutic targets for recurrent GBM a better understanding of its molecular landscape is necessary. Here we used a cellular model, developed in our lab which generates paired primary and recurrent samples from GBM cell lines and primary patient samples hence allowing us to compare the molecular differences between the two populations. Total RNA seq analysis of parent and recurrent population of two cell lines and one patient sample revealed a significant upregulation of Extracellular matrix interaction in recurrent population. Since matrix stiffness plays a pivotal role in cell-ECM interaction and downstream signaling, we developed a system that mimicked the brain like substrate stiffness by using collagen coated polyacrylamide-based substrate whose stiffness can be modified from normal brain (0.5kPa) to tumorigenic (10kPa). Using these substrates, we were able to capture the morphological and physiological differences between parent and recurrent GBM which were not evident on plastic surfaces (~1 GPa). On 0.5kPa, unlike circular parent cells, recurrent GBM cells showed two morphologies (circular and elongated). The recurrent cells growing on 0.5kPa also showed higher proliferation, invasion, migration and in-vivo tumorigenicity in orthotropic GBM mouse model, compared to parent cells. Furthermore, recurrent cells exhibited elevated velocity irrespective of substrate stiffness, which indicated that recurrent cells may possess inherent differential mechanosignalling ability which was reflected by higher expression of ECM proteins like Collagen IVA, MMP2 and MMP9. Moreover, mice brain injected with recurrent cells grown on 0.5kPa substrate showed higher Young’s modulus values suggesting that recurrent cells conditioned on 0.5kPa make the surrounding ECM stiffer. Importantly, inhibition of EGFR signaling, that is amplified with tissue stiffening in GBM resulted in decreased invasion, migration and proliferation in 0.5kPa recurrent cells, but interestingly survival remained unaffected, highlighting the importance of mimicking the physiological stiffness of the brain mimicking clinical scenario. Total RNA seq analysis of parent and recurrent cells grown on plastic and 0.5kPa substrate identified PLEKHA7 as significantly upregulated gene specifically in 0.5kPa recurrent sample. Higher protein expression of PLEKHA7 in recurrent GBM as compared to primary GBM was validated in patient biopsies. Accordingly, PLEKHA7 knockdown reduced invasion and survival of recurrent GBM cells. Together, these data provides a model system that captures the differential mechanosensing signals of primary and recurrent GBM cells and identifies a novel potential target specific for recurrent GBM.

Dataset Information

Glioblastoma-derived migrasomes promote migration and invasion by releasing PAK4 and LAMA4

Publications

Glioblastoma-derived migrasomes promote migration and invasion by releasing PAK4 and LAMA4.

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