(Inter)Facing mechanotransduction-related aspects of brain tumour cell metastasis and therapeutic resistance

Nowadays, it becomes increasingly evident that it is not sufficient to only look at genetic and biochemical factors to fully understand brain cancer and metastases, but that also mechanical aspects of the cells and their extracellular matrix need to be considered. This holds particularly true with respect to the outcome of related cancer treatments.

However, there is only partial understanding of the underlying intricate phenomena of mechanotransduction [1][2], i.e. the integrin adhesion complex (IAC)-mediated conversion of biophysical cues in the cell/microenvironment interface into cellular responses through a force-based dialogue. Strong indications, such as deregulation of mechanotransductive signalling pathways and structures (such as IAC and the glycocalyx), suggest an involvement of mechanotransduction in metastasis and therapeutic resistance of primary brain tumours, such as medullo (MB)- and glioblastoma (GB).

This project aspires to dissect the highly dynamic mechanotransduction-related events in the brain cancer cell/microenvironment interface and their contribution to medullo- and glioblastoma pathophysiology and therapeutic resistance. For this purpose, biophysical features of native extracellular matrix (ECM) of MB and GB brain tumour sites will be analysed and mimicked by engineered biomaterials in which mechanotransductively relevant parameters (e.g., the nanotopography) will be manipulated.

MB and GB cells will be challenged with these substrates, in the presence or absence of typical therapeutic treatments, and a multi-technique strategy will monitor the impact on mechanotransductive processes, focussing particularly on the IAC-mediated cell/microenvironment interface. The analyses will comprise advanced bioimaging (optical, electron and atomic force microscopy (AFM); integrating novel approaches, see [3],[4], and [5]), to detect changes along the mechanotransductive sequence related, e.g., to dynamics and force loading within IAC and the cytoskeletal organisation/mechanics, as well as alterations in response to therapeutic treatments.

Key mechanotransductive regulators will be targeted by enzymatic treatments, RNAi or chemical inhibition/activation to determine their mechanistic role in brain tumour cell pathophysiology and therapeutic resistance. References:

[1] Schulte C, Chapter 4.6 - Mechanotransduction. (2023) Book published by De Gruyter: Mechanics of Cells and Tissues in Diseases Vol. 2, doi (chapter): 10.1515/9783110989380-006

[2] Chighizola M et al., Mechanotransduction in neuronal cell development and functioning. (2019) Biophysical Reviews; doi: 10.1007/s12551-019-00587-2

[3] Holuigue H et al., Native extracellular matrix probes to target patient- and tissue-specific microenvironment interactions by force spectroscopy. (2023) Nanoscale, doi: 10.1039/D3NR01568H

[4] Chighizola M et al., The glycocalyx affects the mechanotransductive perception of the topographical microenvironment. (2022) Journal of Nanobiotechnology; doi: 10.1186/s12951-022-01585-5

[5] Schulte C et al., Conversion of nanoscale topographical information of cluster-assembled zirconia surfaces into mechanotransductive events promotes neuronal differentiation. (2016) Journal of Nanobiotechnology; doi: 10.1186/s12951-016-0171-3