Plasticity of cancer invasion, metastasis and therapy response
Cancer invasion and metastasis arise from a multi-step program of tissue penetration by single cell or collective invasion, which depend on coordination of cell shape, deformability and actin dynamics relative to the tissue environment. We applied a multi-scale approach of intravital multiphoton second and third harmonic generation and fluorescence microscopy, 3D electron microscopy and targeted therapy to identify the key steps of invasion, metastatic escape and cross-talk of invasion programs with therapy resistance. As main routes, non-destructive contact-guidance is mediated by preformed multi-interface 1D, 2D and 3D tissue topologies . This results in adaptive cancer cell responses and programming of collective invasion modes, either as multicellular dynamic networks, or as compact multicellular invasion strands . For collective invasion, the invasion pattern includes a range of cell-cell interaction mechanisms, including adherens junctions, gap junctions and yet unclear low-adhesive interactions supported by high cell density and tissue confinement [1, 2]. 3D ultrastructural analysis reveals predefined tissue conduits (“highways”) of defined geometry, nanotropography and molecular composition or complex interstitial networks of collagen fibers or astrocytic structures as predominant routes of invasion. Invasion niches mediated resistance to radiation therapy, and multi-targeted interference against beta1/alphaV/beta3/beta5 integrins, but not single-targeted therapy, eradicated the resistance niche . In conclusion, cancer invasion is maintained by physicochemical programs that balance cell-intrinsic adhesion and mechanocoupling with encountered physical space and molecular cues which cross-talk to therapy resistance.
1. Van Helvert S, Storm C, Friedl P. Mechanoreciprocity of cell migration. Nat Cell Biol, 20, 8-20, 2018.
2. Gritsenko PG, Atlasy N, Dieteren CEJ, Navis AC, Venhuizen J-H, Veelken C, Schubert D, Acker-Palmer A, Westerman BA, Wurdinger T, Leenders W, Wesseling P, Stunnenberg HG, Friedl P. (2020) P120-catenin dependent collective brain infiltration by glioma-cell networks. Nat Cell Biol, 22(1):97-107.
3. Haeger A, Alexander S, Vullings M, Kaiser FMP, Veelken C, Flucke U, Koehl GE, Hirschberg M, Flentje M, Hoffman RM, Geissler EK, Kissler S, Friedl P Collective cancer invasion forms an integrin-dependent radioresistant niche. J Exp Med 217(1). pii: e20181184, 2020
Dr. Friedl was born and raised in Germany, received his M.D. degree from the University of Bochum in 1992 and the Ph.D. degree from the McGill University, Montreal in 1996. Since 2007 he is directing the Microscopical Imaging Centre of the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and since 2011 holds a joint-faculty position at the University of Texas MD Anderson Cancer Center, Houston, TX for preclinical intravital imaging of cancer lesions and their response to molecular targeted and immunotherapy. His research interest is the mechanisms and plasticity of cell migration in immune regulation and cancer metastasis, with emphasis on cell-matrix adhesion, pericellular proteolysis and cell-cell communication during migration.
His laboratory identified pathways determining diversity and plasticity of cell migration, collective cancer cell invasion, and the contribution of migration pathways to immune defense and cancer resistance. His discoveries have provided a nomenclature for the different types of cell migration and their roles in building and (re)shaping tissue, with emphasis on inflammation, regeneration and cancer. His therapeutic preclinical studies focus on the intravital visualization of niches and mechanisms and strategies to overcome therapy resistance.