Jasmin Kaivola from the Ivaska lab successfully defended her PhD thesis “Biomechanical Tumour Matrix” on Friday the 29th of November 2024. Her opponent was Professor Rachel Lennon from the Cell-Matrix Research Center, University of Manchester, UK.

Summary of the Dissertation:

The interplay between mechanical forces and the tumour microenvironment is critical in cancer progression, influencing tumour growth, metastasis and therapy resistance. Integrins, which mediate cell adhesion to the extracellular matrix (ECM), transmit mechanical signals that regulate key cellular processes including proliferation and migration. These mechanical forces modulate integrin activity, altering the cytoskeleton and signalling networks, thereby promoting cancer invasiveness and metastasis. The tumour matrix’s physical properties, such as stiffness, further drive cancer progression. Cancer-associated fibroblasts remodel the ECM, increasing matrix stiffness and enhancing mechanotransduction pathways. Moreover, cancer-associated adipocytes contribute to metabolic reprogramming and inflammation, creating a feedback loop that accelerates tumour growth. Understanding these molecular mechanisms is crucial for developing therapies that disrupt these pathways to inhibit cancer progression and metastasis.

In this thesis, I have explored how reintroducing mechanical forces lost in cancer, owing to increased tissue rigidity, can downregulate oncogenic signalling activity. Specifically, stretching and vibrating vocal fold cancer cells lead to nucleocytoplasmic localisation of the oncogenic transcription factors YAP/TAZ and β-catenin. Additionally, I have investigated the role of healthy adipocytes in the breast tumour microenvironment, demonstrating that secretion of the adipocrine factor IGFBP2 can act as a protective barrier against breast cancer progression. Lastly, I examined the role of the integrin inactivator SHANK3 in KRAS-driven cancers, showing that disrupting the SHANK3-KRAS interaction can induce cell death in KRAS-mutant cancer cells through hyperactivation of the MAPK-ERK pathway. Collectively, these findings offer novel strategies to inhibit and target cancer progression across different cancer types.

Download Doctoral Dissertation at UTUPub: https://urn.fi/URN:ISBN:978-951-29-9938-5