Microenvironmental containment of tumours

Microenvironmental containment of tumours image

We have previously uncovered key differences between normal and cancer-associated stroma, whereby the mechanical and architectural features of normal stroma inhibit tumour growth and may epigenetically reprogram aggressive breast cancer cells towards a more benign phenotype. Recently, we turned our attention to other putative crosstalk mechanisms between cancer cells and the microenvironment. We discovered that normal stromal components can also inhibit cancer cell invasion and migration towards the vasculature. We are now investigating the mechanisms for this in a newly funded Worldwide Cancer Research project.

Related publication from the lab
  1. Conway et al., Science Advances (2023)
  2. Kaukonen et al., Nature Communications (2016)

Cell adhesion and cancer

Cell adhesion and cancer image

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 fate 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 publication from the lab
  1. Salomaa et al., Current Biology (2021)
  2. Miihkinen et al., Cell Reports (2021)
  3. Taskinen et al., Journal of Cell Biology (2020)

Integrin trafficking

Integrin trafficking image

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 publication from the lab
  1. Moreno-Layseca et al., Nature Cell Biology (2021)
  2. Sahgal P et al., Journal of Cell Science (2019)
  3. Moreno-Layseca et al., Nature Cell Biology (review) (2019)

Receptor tyrosine kinase trafficking

Receptor tyrosine kinase trafficking image

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 publication from the lab
  1. Al Akhrass et al., Molecular Oncology (2021)
  2. Al Akhrass et al., Oncogene (2021)
  3. Pietilä et al., Nature Communications (2019)

Biophysical regulation of cancer cells

Biophysical regulation of cancer cells image

The cells of a multicellular organism will encounter a wide range of biophysical cues, ranging from tensile and compressive forces to the architecture and visco-elasticity of the surrounding extracellular matrix. Such mechanobiological interactions can directly impact cell signaling and function, including the survival, growth and motility of individual cancer cells. Despite this, the nature of many biomechanical signals and how they are interpreted by the cells remain poorly understood. We work on that! For example, healthy extracellular matrix can have an anti-tumorigenic function through epigenetic regulation (Kaukonen et al. 2016). Substrate mechanics can also influence cell migration directly, as many cell types are known to sense and move toward stiffer matrix; this process is called durotaxis. Similar gradients are found in tumors, and we have now uncovered a previously unappreciated capacity of cancer cells to migrate against stiffness gradients, toward softer environments, to reach a sitffness optimum. Finally, while many studies so far have focused on the elastic properties of the matrix, some tissue types are also naturally exposed to more dynamic forces. We are studying how such mechanical perturbations can influence tumorigenesis and, conversely, how tissue mechanics may be influenced by tumor progression.

Related publication from the lab
  1. Isomursu et al., Nature Materials (2022)
  2. Kaukonen et al. Nature Communications (2016)

Imaging metastasis

Imaging Metastasis image

Circulating tumor cells are able to 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 publication from the lab
  1. Jacquemet et al., Current Biology (2019)
  2. Jacquemet et al., Journal of Cell Biology (2017)
  3. Jacquemet et al., Nature Communications (2016)

Tools for mechanobiology

Tools for Mechanobiology image

Due to our continued interest in untangling the mechanobiological pathways that regulate cancer cell behaviour, we are always expanding our toolbox for interrogating and controlling the different biophysical features of cells and their environment. Through vital collaborations and in-house method development, we seek to improve the biological relevance of our experiments. Some examples of new methodology include super-resolution traction force microscopy, used for measuring the contractile forces exerted by individual cells on their surroundings; stiffness gradient hydrogels, for studying how substrate mechanics can direct cell-matrix interactions and migration; new micropatterning applications, for controlling cancer cell morphology and dynamic interactions with different extracellular matrix components; and microfluidic shear stress modeling, for studying cancer cell intravascular adhesion.

Related publication from the lab
  1. Isomursu et al., (2022), Nature Materials
  2. Stubb et al., (2020), Nano Letters
  3. Nuria Barber-Perez (2020), Journal of Cell Science

The link between cell states and disease

The link between cell states and disease image

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)