The Membrane Integrity Group specializes in molecular mechanisms of membrane repair and cell death signaling in cancer cells. Our research aims to understand cell repair mechanisms in cancer and other human disorders while exploring new ways to target cancer cells by compromising their membrane integrity.
Our interdisciplinary team includes experts in molecular and cellular cancer biology, theoretical/experimental physics, and computer simulations, with a particular focus on live-cell imaging techniques. Through frequent collaboration with international researchers, we create a unique platform for innovative research in the emerging field of cancer cell membrane repair.
By combining sophisticated physical methods and concepts such as membrane curvature, protein and lipid organization, and predictive molecular simulations, we gain detailed mechanistic insight into repair mechanisms and aim at developing targeted strategies for cancer treatment.
Single Cell Repair: Unveiling Cancer Cell Membrane Mechanisms
During evolution, eukaryotic cells evolved repair mechanisms to combat plasma membrane disruptions and avoid cell death. In our research, we've discovered that cancer cells depend on efficient plasma membrane repair to survive the stress-induced damage caused by metabolic stress, membrane dynamics, and navigating dense extracellular matrices.
Despite experiencing more membrane damage, cancer cells respond by upregulating components of their repair machinery to counteract injuries. This repair system involves various mechanisms, such as organelle-mediated wound patching, cytoskeleton remodeling, annexin complexes facilitating membrane fusion events, and damaged membrane excision and shedding.
Though not fully characterized yet, this repair system holds significant importance for cancer cell survival and is also relevant in various disorders with deficient repair, including muscular dystrophy, heart failure, and neurodegenerative disorders. To address this, we focus on studying cancer-associated cell membrane repair mechanisms using molecular biology techniques, advanced live-cell imaging, and biophysical models.
Our goal is to gain comprehensive mechanistic insight into the repair system and develop innovative strategies to hinder cell membrane repair, paving the way for future cancer therapies.
Plasma Membrane Repair: Role of Annexin Proteins
(A) Sequential 3D-images of a breast cancer cell (MCF) demonstrate the localization of annexin A6 (ANXA6-GFP) and annexin A4 (ANXA4-RFP) in response to laser injury (white arrow indicates injury site). A repair cap, 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 uniformly distributed as monomers in the cytoplasm. Upon local plasma membrane injury, Ca2+ influx recruits ANXA6 and ANXA4 to the wound edges. ANXA6 initiates hole edge constriction and may cross-bridge patch-vesicles translocated to the injury site. ANXA4 self-assembles into trimers inducing local curvature. Constriction and curvature forces accelerate wound closure, leading to membrane edge fusion. Vesicles fused to the wound edges contribute to repair by reducing wound size.
(C) Illustration of an initial and curved state of a circular membrane hole. The solid area inside the circle indicates the region contributing to the change in curvature elastic energy between the 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).
Group leader: Jesper Nylandsted
Jesper Nylandsted earned his diploma in Biology (Qualification Profile in Cell and Molecular Biology), and his PhD from University of Copenhagen, Faculty of Health Sciences.
After finishing his Postdoc studies at the Danish Cancer Society and the Rockefeller University (New York), he served as Senior Scientist before starting his own research group at the Danish Cancer Institute in Copenhagen.
Jesper Nylandsted has a strong background in Cell Death Pathways and Repair Mechanisms of Cancer Cells with a special interest in integrating different Interdisciplinary Research Fields including Molecular Biology, Physics and Computational Science. Interdisciplinary collaborations to achieve unique insights is at the core of his work.
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