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Cell adhesion and cancer
Tissue homeostasis is dependent on the spatially controlled localization of specific cell types and the correct composition of the extracellular stroma. Integrin mediated adhesions, in conjunction with the actin cytoskeleton, regulate cell faith and identity and allow cells to migrate and invade the surrounding extra-cellular matrix (ECM). Tight control over integrin mediated adhesion and signalling is paramount for normal cell function and is perturbed in almost every step of cancer progression. Our long-standing interest is in uncovering cancer relevant integrin-associated proteins and signalling networks. We have used RNAi screens to identify new proteins implicated in the regulation of integrin activity, integrin traffic, cell migration and metastasis. We are continuing this work by 1) investigating in mechanistic detail adhesion regulating protein networks using proximal-biotinylation, by 2) developing FRET-based probes to map the spatiotemporal regulation of integrin signalling under different conditions, by 3) screening for cell response to varying ECM compositions.
Related publications from the lab: Salomaa et al., 2021 Curr Biol (will be published 4.10); Miihkinen et al., 2021 Cell Reports, Taskinen et al., 2020 JCB, 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 most recent work has identified key roles for actin-binding protein swiprosin-1 in directing integrin endocytosis to the CG-pathway thus promoting integrin endocytosis and cell migration. Accordingly, high levels of swiprosin-1 correlates with a significant increase in breast cancer metastasis in large cohort of triple-negative breast cancer.
Related publications from the lab: Moreno-Layseca et al., (2021) Nat Cell Biol; 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: Al Akhrass et al., (2021), Mol. Onco.; Al Akhrass et al., (2021), Oncogene; Pietilä et al., (2019), Nat Commun; Barrow-McGee et al., (2016), Nat Commun; Muharram et al., (2014) Dev Cell.
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., (2020), Nano Letters; Nuria Barber-Perez (2019), BioRxiv
Imaging of Metastasis
Circulating tumor cells are able the stop in small capillaries, engage stable adhesions with endothelial cells and transmigrate through the vessel walls. These are key steps of the metastatic cascade that are still poorly understood. Nonetheless, they directly precede the formation of life-threatening metastases. We develop microfluidic models and use in vivo models to study the fundamental aspect of these steps in relevant biomechanical conditions. Of particular interest, we study the role of filopodia-like protrusions and the adhesion receptors decorating them, as well as the key role of endothelial cells as a barrier against metastatic spreading. The project is running in close collaboration with the Jacquemet lab.
This project is supported by two recent and important funding source : JAES foundation until 2025 and the formation of the new Center of Excellence from Academy of Finland – BarrierForce until 2029 !
Related publications from the lab: Jacquemet et al., (2019), Curr Biol; Jacquemet et al., (2017), J Cell Biol; Jacquemet et al., (2016), Nat Commun.
Translational cancer drug discovery
One of the key focus areas of the laboratory is to take fundamental research discoveries in cancer cell biology towards translation. We have currently two ongoing drug discovery projects linked to ERC Proof-of-concept funding:
SaveHER – The inhibition of sorting proteins as a therapeutic avenue in HER2 positive breast cancer
Research from our laboratory has uncovered novel therapeutic targets in cancer. We have focused on HER2 trafficking in the context of HER2-amplified cancers and identified a supporting role for the sorting protein SORLA in the recycling and concogenic signalling of HER2 and HER3 receptor tyrosine kinases back to the plasma membrane. We have shown that disrupting SORLA-dependent recycling compromises the oncogenic fitness of HER-driven breast and bladder cancer in vitro and in vivo. Furthermore, SORLA-depletion re-sensitises anti-HER2 therapy resistant breast cancer cells to therapy and limits expansion of brain metastasis. We have recently generated a function-blocking antibody against SORLA and demonstrated efficacy in xenografts and primary patient derived explant cultures. In our ongoing drug discovery programme, we are further delineating the mechanism of SORLA action in HER2 therapy resistance and developing anti-SORLA therapy.
Related publications from the lab: Al Akhrass et al., (2021), J. Mol. Onco.; Al Akhrass et al., (2021), Oncogene; Pietilä et al., (2019), Nat. Comm.
RASaTAC – Regulating RAS Activity to Target RAS-Driven Cancers
RAS are a family of genes whose mutations are implicated in a variety of different cancers. Despite their ubiquitous oncogenic activity, no effective anti-RAS therapies exist today. Prior work by us had shown that a class of scaffold proteins bind to mutated forms of RAS proteins. In cancer this interaction moderates RAS signaling and triggers cytotoxic signalling and leads to cell death. We are currently working in collaboration with a biotech start-up company plan to develop drugs that mimic the activity of these scaffold proteins as an innovative approach to target RAS-driven cancers. The results will offer a novel cancer treatment option to patients that do not respond to current standards of care.
Related publications from the lab: Lilja et al., (2017), Nat. Cell Bio.
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.
This area of our research is supported by Academy of Finland. Funded research program: Molecular Regulatory Networks of Life (R’Life) 2020–2023. Nucleomechanical regulation of cell states – from pluripotency to cancer (NucleoMech)
Our research is only possible because of our generous 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 Finnish Cancer Foundation and the Sigrid Juselius Foundation.