As soon as normal tissue organization within a tumour breaks down cancer cells are thought to be able to migrate out by degrading the surrounding extracellular matrix or moving along channels in the tissue. Irrespective of the degradative ability, all cancer cells have to be able to migrate efficiently in a directional manner to complete the first step of the metastatic cascade -the invasion into surrounding tissues. Cell migration on a two-dimensional (2D) surface, mostly cell culture dishes, has been studied extensively and is driven by a well characterised mechanism involving basal adhesion sites called focal adhesions, actin driven protrusions called lamellipodia and actomyosin contractile forces. In contrast, the mechanisms of directional protrusive migration in drastically different three-dimensional (3D) tissue environments are not understood on a molecular level.

One of the major roadblocks to successful 3D matrix migration of cancer cells is the need to deform and move the nucleus forward when migrating in geometrically confined tissue with dense cross-linked extracellular matrix (ECM). For effective 3D matrix migration the outer nuclear membrane needs to be coupled to the cytoskeleton through a family of proteins called Nesprins. The n-terminal domains of Nesprins bind to the cytoskeleton whereas the c-terminal KASH domains bind SUN domain protein in the nuclear intramembrane space to transduce force into the nucleus and affect the nuclear cytoskeleton. Actomyosin based force transmission into the nucleus has been shown to affect both the expression profile of nuclear structural components, like lamin A/C and also to initiate oncogenic global changes in gene transcription though tension sensitive transcription factors like YAP/TAZ and Twist.

 
Nothing is known about how ECM-adhesion complexes regulate nucleo-cytoplasmic force coupling (NFC) in invasive cancer cell migration and how this affects cell migration in 3D environments. It is a central unanswered question in tumour cell biology, how interactions with tumour and normal tissue ECM are relayed into tension dependent signals that are required for invasion of cancer cells.  

We are investigating the composition and function of 3D matrix adhesion sites in invasive cancer cells to decipher how nuclear force coupling drives invasive cell migration and metastatic cancer progression.