Tight control over integrin signalling is paramount for normal cell function and is perturbed in almost every step of cancer progression. Integrin heterodimers can exist in a bent/closed conformation with low affinity for extracellular ligands (‘inactive’) or in an extended/open conformation with a high affinity for ligands (‘active’). Because of this conformational switch, integrins are able to transmit signals bidirectionally across the cell membrane. We have used RNAi screens to identify new proteins implicated in the regulation of integrin activity. We are continuing this work by expanding on our siRNA screens and by developing FRET-based probes to map the spatiotemporal regulation of integrin signalling under different conditions.
Related publications from the lab: Rantala et al., (2011) Nat Cell Biol; Lilja et al., (2017), Nat Cell Biol; Georgiadou et al., (2017) J Cell Biol.
We also focus on identifying integrin-specific regulators that impinge on integrin trafficking pathways to provide a means to selectively target integrins. We have adopted several techniques to study integrin trafficking including the retention using selective hooks (RUSH) system, which can be used to study synchronised receptor recycling under different conditions (e.g. on different extracellular matrix ligands; drug stimulation; loss or gain of function experiments). In addition, we have performed both siRNA screens and comprehensive mass spectrometric analyses of integrin trafficking regulators and our unpublished work has identified key roles for several actin-binding proteins in promoting integrin endocytosis.
Related publications from the lab: Sahgal P et al., (2019), J Cell Sci; Moreno-Layseca et al., (2019) Nat Cell Biol (review); Hamidi H, Ivaska J (2018), Nat Cancer Reviews; Alanko et al., (2015), Nat Cell Biol.
Receptor tyrosine kinase trafficking
There is increasing evidence linking oncogenic signalling of specific RTKs (e.g. MET and EGFR) with their intracellular traffic. We are focusing on HER2 trafficking in the context of HER2-amplified cancers and recently identified a supporting role for the sorting protein SORLA in HER2 recycling back to the plasma membrane. We found that disrupting SORLA-dependent recycling promotes lysosomal dysfunction and sensitises HER2-amplified cancer cells to lysosome-targeting cationic amphiphilic drugs. In our ongoing drug discovery programme, we are further delineating the mechanism of SORLA action in HER2 therapy resistance.
Related publications from the lab: Pietilä et al., (2019), Nat Commun; Barrow-McGee et al., (2016), Nat Commun; Muharram et al., (2014) Dev Cell.
The link between cell states and disease
Embryonic stem cells actively shape their microenvironment and dynamically alter their own state to form organized tissue patterns. Cancer cells bear resemblance to stem cells in their plasticity and ability to adapt to new tissue compositions during metastasis. In contrast, this fundamental property is lost in differentiated cells, which stably maintain their committed state, guided by pre-existing tissue architecture. In collaboration with the Wickström and Mäkitie groups we have launched an exciting new dimension to our research to understand which factors allow cancer cells to bypass established cell-state and tissue barriers, and to explore the possibility to drive cancerous, stem-like states towards normal morphogenesis to limit disease progression.
Mechanobiology of cancer – toolbox
We have a keen interest in untangling the crucial mechanobiological pathways regulating cancer cell behaviour and this has become a central part of many of our investigations. To this end, we are expanding our toolbox, both through vital collaborations and through method development, to improve the biological relevance of our experiments (i.e. application of force, tuning force dynamics and the analysis of the mechanoresponse). Examples of our method development include: superresolution traction force microscopy, stiffness gradient hydrogels and micropatterning.
Related publications from the lab: Stubb et al., (2019), BioRxiv; Nuria Barber-Perez (2019), BioRxiv
Integrins in filopodia adhesions
Filopodia are important finger-like cellular protrusions that probe and then relay microenvironmental details back to the cell during normal processes such as development and wound healing. However, filopodia and filopodia-like structures are also implicated in cancer progression. Since filopodia contain integrin receptors and integrins are the primary contact between the extracellular space and the cell’s cytoskeleton, we are aiming to get a better understanding of how these receptors are regulated in filopodia both in terms of activation and transport to filopodia tips. This work is in collaboration with the Jacquemet lab.
Related publications from the lab: Jacquemet et al., (2019), Curr Biol; Jacquemet et al., (2017), J Cell Biol; Jacquemet et al., (2016), Nat Commun.
hiPSC adhesions, cytoskeleton and pluripotency
Pluripotent stem cells can differentiate into all cell types of the human body and therefore hold great promise for regenerative medicine. Our data suggest that focal adhesion architecture and cytoskeletal contractility are important gatekeepers of human pluripotent stem cell (hPSC) differentiation. Our superresolution microscopy analyses (interferometric photoactivated localization microscopy; iPALM) also demonstrate the unique nanoscale organization of hPSC focal adhesions, the cell’s mechanotransducing units, and their actin linkage. Our ongoing work aims to define how integrin-mediated adhesions control cell states and impact on pluripotency.
Related publications from the lab: Stubb et al., (2019), Nat Commun; Närvä et al., (2017), Stem Cell Reports.
Thanks to Our Funders
Our projects have received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme, the Academy of Finland, the Cancer Society of Finland and the Sigrid Juselius Foundation.