Membrane Integrity

Group leader: Jesper Nylandsted

The Membrane Integrity Group has extensive expertise within molecular mechanisms of membrane repair and cell death signaling in cancer cells. Our research focuses on cell repair mechanisms in cancer and other human disorders, and novel approaches to target cancer cells by compromising membrane integrity.

The group is characterized by strong interdisciplinary research within molecular and cellular cancer biology, theoretical/experimental physics, and computer simulations, with a core expertise in live-cell imaging techniques. We have frequent exchange of researchers and a high degree of international collaboration.

We believe that the combination of scientific disciplines offers a unique platform to perform innovative research within the nascent field of cancer cell membrane repair. Detailed mechanistic insight into repair mechanisms and targeting of these processes can only be fully resolved by incorporating sophisticated physical methods and concepts like membrane curvature, protein and lipid organization, paralleled by the use of predictive molecular simulations. 

Membrane Integrity test

Figure 1

Plasma membrane injury and repair by annexin proteins. (A) Representative sequential 3D-images of a breast cancer cell (MCF) showing the localization of annexin A6 (ANXA6-GFP) and annexin A4 (ANXA4-RFP) in response to laser injury (white arrow indicate injury site). Cells were injured by shooting through the cell to obtain a hole with clear edge. A putative repair cap defining where the edges have fused is visible in the middle (yellow arrow). (B) Proposed model for plasma membrane repair initiated by ANXA4 and ANXA6. In uninjured cells, ANXA6 and ANXA4 are distributed uniformly as monomers in the cytoplasm. Upon local plasma membrane injury, Ca2+ influx results in recruitment of ANXA6 and ANXA4 to the membrane wound edges. ANXA6 initiates constriction of hole edges and may also cross-bridge patch-vesicles translocated to the injury site. ANXA4 self-assembles into trimers that induce local out-of-plane curvature. The combined forces of constriction and curvature accelerate wound closure eventually leading to fusion of membrane edges. Vesicles recruited and fused to the wound edges contribute to repair by reducing wound size. (C) Initial and curved state of a circular membrane hole. The solid area inside the solid circle is the region contributing to the change in curvature elastic energy between the initial and curved states. (D) Profile of the neck and definitions: initial hole radius r0, the neck angle Δ and curvature radius B. (Boye et al., 2017. Nature Commun).

Single Cell Repair 
During evolution eukaryotic cells have developed repair mechanisms to counteract death triggered by plasma membrane disruptions.

We have discovered that cancer cells are more dependent on efficient plasma membrane repair to cope with stress-induced membrane lesions, which are caused from enhanced metabolic stress, membrane dynamics and from navigating through dense extracellular matrix. Although cancer cells experience more membrane damage they respond by upregulating components of their repair machinery to counteract membrane injuries.

The repair system involves several mechanisms including wound patching by organelles, remodeling of cytoskeleton, membrane fusion events facilitated by annexin complexes and membrane replacement by excision and shedding of damaged membrane.

The repair system is, as yet, not well characterized in cancer cells but is important for their survival and also relevant for several other disorders implicating deficient repair including, muscular dystrophy, heart failure and neurodegenerative disorders. 
For this purpose we study cancer-associated cell membrane repair mechanisms using molecular biology methods, advanced live-cell imaging and biophysical models.

Our goal is to reveal comprehensive mechanistic insight into the repair system and develop novel strategies to inhibit cell membrane repair for future cancer therapy. 


Selected publications:

Bendix PM, Simonsen AC, Florentsen CD, Häger SC, Mularski A, Zanjani AAH, Moreno-Pescador G, Klenow MB, Sønder SL, Danielsen HM, Arastoo MR, Heitmann AS, Pandey MP, Lund FW, Dias C, Khandelia H, Nylandsted J: Interdisciplinary Synergy to Reveal Mechanisms of Annexin-Mediated Plasma Membrane Shaping and Repair. Cells 2020;9(4):1029

Boye TL, Maeda K, Pezeshkian W, Lauritzen SP, Hager SC, Gerke V, Simonsen AC, Nylandsted J: Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair. Nature Commun 2017;8(1):1623

Jaiswal JK, Lauritzen SP, 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 Commun 2014;5:3795

Petersen NH, Olsen OD, Groth-Pedersen L, Ellegaard AM, Bilgin M, Redmer S, Ostenfeld MS, Ulanet D, Dovmark TH, Lønborg A, Vindeløv SD, Hanahan D, Arenz C, Ejsing CS, Kirkegaard T, Rohde M, Nylandsted J, Jäättelä M: Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 2013;24(3):379-393

Kirkegaard T, Roth A, Petersen NHT, Mahalka AK, Olsen OD, Moilanen I, Zylicz A, Knudsen J, Sandhoff K, Arenz C, Kinnunen PKJ, Nylandsted J, Jäättelä M: Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology. Nature 2010;463(7280):549-553


 

Group leader Jesper Nylandsted
Research profile

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Membrane Integrity
Staff Members


Key Funding

Novo Nordisk Foundation, Interdisciplinary Synergy Grant

The Danish Cancer Society Scientific Committee

Independent Research Fund Denmark, DFF Natural Sciences & DFF Medical Sciences

Krista and Viggo Petersens Foundation