The Membrane Integrity Group

Why Plasma Membrane Repair?

Maintaining integrity of the plasma membrane is essential for cancer cells during metastasis (spread to other parts of the body) where they need to cope with wear-and-tear injuries, as well as more traumatic membrane injuries. Even in the protective environment of a tissue, various mechanical and chemical stresses can damage a cell’s plasma membrane. Accordingly, cells require dedicated membrane repair machinery to survive and recover from membrane wounding. We have discovered that invasive cancer cells are even more dependent on efficient plasma membrane repair to cope with increased motility, membrane dynamics and malfunctions associated with enhanced membrane stress. Further, this system is important during invasion through dense extracellular matrix where metastatic cancer cells are exposed to significant membrane stress which can lead to stretch-induced membrane ruptures. If these wounds are not repaired instantly cancer cells will be unable to invade and eventually die. Cancer cells compensate and counteract membrane stress by up regulating components of the membrane repair system.

Research Aims

Our major goal is to identify plasma membrane repair targets and develop novel membrane-repair cancer therapies. For this purpose we study cancer-associated changes in proteins recruited or associated with the plasma membrane after different membrane injuries and changes in lipid composition and trafficking. We analyze repair components and screen for drugs that directly interferes with cancer plasma membrane integrity by restricting cell healing. To study these processes we use state of the art live cell imaging. In addition, we investigate cancer membrane repair in connection with other organelles including lysososome membrane integrity and death pathways activated by lysosomal membrane permeabilisation.

Background

Plasma membrane injuries are frequent in cells that are exposed to stressful conditions and thus efficient wound healing is crucial for cells to sustain viability. Functional deficiencies in plasma membrane maintenance or repair in active cells such as muscle cells is associated with muscular dystrophy diseases that lead to muscle destabilization and fragility. In case of smaller injuries damaged membrane can be repaired by spontaneous lipid flow across the injured site, endocytic uptake of the pore, outward budding of the damaged membrane, and by exocytic fusion of lysosomes and other cytosolic vesicles.

The trigger of plasma membrane repair (PMR) is Ca²⁺ influx at the injury site, which can facilitate cytoskeletal reorganization and membrane fusion events. Presence of cortical cytoskeleton associated with the plasma membrane creates membrane tension, which prevents spontaneous resealing of the membrane. Thus, spatial and temporal remodeling of cortical cytoskeleton at the wound site is essential for efficient PMR after bigger injuries. In addition, PMR requires a coordinated effort of annexin-containing multiprotein complexes at the inner phospholipid surface to seal a wound. Here, members of the annexin (ANXA) protein family function as intracellular Ca²⁺ sensors and repair proteins. They interact with multiple proteins and distinct anionic phospholipids to promote membrane fusion, vesicle fusion as well as membrane and cytoskeletal organiza­tion in a Ca²⁺-dependent manner.

Local Ca²⁺ influx also causes members of the S100 family of Ca²⁺ binding proteins to undergo a conformational change, enabling them to interact with some annexins, such as ANXA1 and ANXA2. This interaction is suggested to facilitate close apposition of adjacent phospholipid membranes during a membrane fusion event. Both ANXA and S100 protein family members are often found highly over expressed in cancer and associated with metastasis.

We have discovered that invasive breast cancer cells are dependent on efficient plasma membrane repair and that they up regulate S100A11 and ANXA2 proteins as part of the repair response. S100A11 is associated with tumor metastasis as well as poor prognosis in various cancers. Injury-induced calcium entry into the cell triggers recruitment of S100A11 and Annexin A2 to the site of injury (Figure 1). Here, S100A11 in a complex with ANXA2 facilitates resealing by enabling polymerization of cortical F-actin around the wound perimeter and excision of the damaged part of the plasma membrane This is the first example of how invasive cancer cells acquire an ability to cope with plasma membrane injuries and reveal PMR in general as an attractive target for the therapy of metastatic cancers:

#Jaiswal JK, Stine P. Lauritzen, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, Kallunki T, Jäättelä M, Nylandsted J. S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nature Communications. 2014. 8;5:3795. doi: 10.1038/ncomms4795.