Like people, cells in the human body protect their personal space. They seem to know how much space they need, and if it gets too tight, most cells prefer to break free. The mechanism enabling cells to evade crowded environments appears to involve an unusual player - the cell nucleus. This is what researchers from St. Anna Children's Cancer Research Institute Vienna, King's College London, Institute Curie Paris, and ETH Zürich in Basel showed in their recent work.
Tissue cells protect their "personal space"
The human body consists of trillions of cells growing in confined volumes, which often leads to cell crowding. The crowding effect is exacerbated when cell growth and proliferation are out of control during tumor formation. This creates a compressive microenvironment for the constituent cells. How do tumor cells cope with the lack of space and compressive stresses? Answering this question, the investigators found that the cells are able to sense environmental compression.
To do so, they utilize their largest and stiffest internal compartment, the nucleus. Squeezing cells to the degree that physically deforms the nucleus causes the nuclear membranes to unfold and stretch. These changes are detected by specialized proteins, activating cellular contractility. The ability to develop contractile forces helps squeezing the cell out of its compressive microenvironment in an "evasion reflex" mechanism. Therefore, the study proposes that the nucleus operates as a ruler (see the accompanying illustration). It allows living cells to measure their personal space and trigger specific responses once the space becomes violated.
Fat restrictions to target metabolic vulnerability in cancer?
As the scientists describe in the paper, Ca2+-dependent phospholipase cPLA2 is a protein, which senses nuclear membrane stretch upon cell compression. The lead author Alexis Lomakin, PhD, emphasizes that cPLA2 represents a druggable target. "Pharmaceutical companies are currently testing small molecule inhibitors of cPLA2. Based on our data, downregulating the activity of cPLA2 in tumor cells might interfere with their ability to escape the primary tumor and metastasize to distant locations", explains Dr. Lomakin.
cPLA2-inhibitors prevent the production of arachidonic acid (ARA), which subsequently affects cell migration, growth, and survival. However, ARA can also be obtained by cells from their environment. The Western diet, for instance, is a potent source of omega-6 fatty acids, such as ARA. Dietary fat restriction and consumption of omega-3 instead of omega-6 fatty acids could synergize with cPLA2 inhibitors to effectively attenuate tumor cell escape from overcrowded areas. "Testing these hypotheses is an exciting direction for future research", concludes Dr. Lomakin.
Potential predictive marker for chemo-resistance
Identifying the cell nucleus as an active player that rapidly converts mechanical inputs into signaling or metabolic outputs is surprising. Until today, the nucleus was considered as a passive storehouse for genetic material. "We are very excited about what comes next", says Dr. Lomakin. According to him, high degrees of nuclear deformation could be predictive of metastatic potential and resistance to chemotherapy and immunotherapy.
"For many years, pathologists have been evaluating changes in the shape of the nucleus to discriminate between different stages of tumor growth; however, how these structural-mechanical alterations of the nucleus functionally impact cancer cells remained completely unexplored", says Dr. Lomakin.
The nucleus acts as a ruler tailoring cell responses to spatial constraints A. J. Lomakin*†‡, C. J. Cattin†, D. Cuvelier, Z. Alraies, M. Molina, G. P. F. Nader, N. Srivastava, P. J. Saez, J. M. Garcia-Arcos, I. Y. Zhitnyak, A. Bhargava, M. K. Driscoll, E. S. Welf, R. Fiolka, R. J. Petrie, N. S. De Silva, J. M. González-Granado, N. Manel, A. M. Lennon-Duménil, D. J. Müller*, M. Piel*‡
†These authors contributed equally to this work.
‡These authors contributed equally to this work.
Science, October 16, 2020
The research leading to these results has received funding from the People Program (Marie Sk?odowska-Curie Actions) of the European Union's Seventh Framework Program, Marie Sk?odowska-Curie Individual Fellowships and a European Molecular Biology Organisation (EMBO) Long-Term Fellowship. This work was further supported by the PRESTIGE program coordinated by Campus France, the Marie Curie and PRESTIGE Fellowship, the Institut Pierre-Gilles de Gennes-IPGG, the Institut National du Cancer and INSERM Plan Cancer Single Cell. Funding was also received from the London Law Trust Medal Fellowship. A Career Grant for Incoming International Talent was provided by the Austrian Research Promotion Agency (FFG). The study was also supported by the National Center of Competence in Research (NCCR) Molecular Systems Engineering, the National Institute of General Medical Sciences, the National Institutes of Health as well as the I3 SNS program. Funding was further received from the Instituto de Salud Carlos III (ISCIII) Additional support was provided by the Metchnikov Fellowship from the Franco-Russian Scientific Cooperation Program and the Russian Science Foundation.
About Alexis Lomakin, PhD
Alexis Lomakin, PhD, is a Program Leader & Deputy Lab Head in the academic group of Prof. Kaan Boztug, MD, at St. Anna Children's Cancer Research Institute/CCRI in partnership with Ludwig Boltzmann Institute for Rare & Undiagnosed Diseases/LBI-RUD, the CeMM Research Institute for Molecular Medicine of the Austrian Academy of Sciences, and Medical University of Vienna (Vienna, Austria). Prior to taking up the position in Vienna, Dr. Lomakin was a Junior Group Leader at King's College London (London, UK) and a Staff Scientist at the Institut Curie (Paris, France). He obtained his PhD in Cellular and Molecular Biology from Lomonosov Moscow State University (Moscow, Russia), and the University of Connecticut (Farmington, CT, USA). Dr. Lomakin pursued his postdoctoral training in Quantitative Cell Biology at Harvard University (Boston, MA, USA).
The scientist received prestigious fellowships and awards including the London Law Trust/LLT Medal and Fellowship for scientific excellence, innovation & vision (UK), the Marie Sk?odowska-Curie and PRESTIGE Fellowships (EU/France), and the Leukemia & Lymphoma Society/LLS Postdoctoral Fellowship (USA).
About St. Anna Children's Cancer Research Institute, CCRI
The CCRI is an internationally renowned multidisciplinary research institution with the aim to develop and optimize diagnostic, prognostic, and therapeutic strategies for the treatment of children and adolescents with cancer. To achieve this goal, it combines basic research with translational and clinical research and focus on the specific characteristics of childhood tumor diseases in order to provide young patients with the best possible and most innovative therapies. Dedicated research groups in the fields of tumor genomics and epigenomics, immunology, molecular biology, cell biology, bioinformatics and clinical research are working together to harmonize scientific findings with the clinical needs of physicians to ultimately improve the wellbeing of our patients.
#ccri #kinderkrebsforschung #stanna
About Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD)
LBI-RUD was founded in 2016 in a joint effort of Ludwig Boltzmann Society, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Medical University of Vienna, and St. Anna Children's Cancer Research Institute. The three founding partner institutions, and CeRUD Vienna Center for Rare and Undiagnosed Diseases, constitute LBI-RUD's most important collaboration partners.
Research at LBI-RUD focuses on the deciphering of rare immunological, hematopoietic, nervous, dermal, gastro-intestinal, and hepatic diseases. Those studies provide unique insights into human biology, and are the basis for the development of tailored therapeutic concepts in the sense of the personalized medicine of the future.
The mission of LBI-RUD is - together with its partner institutions - to sustainably develop and maintain research infrastructure integrating scientific, societal, ethical, and economical aspects of rare diseases.
About CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
The mission of CeMM is to achieve maximum scientific innovation in molecular medicine to improve healthcare. At CeMM, an international and creative team of scientists and medical doctors pursues free-minded basic life science research in a large and vibrant hospital environment of outstanding medical tradition and practice. CeMM's research is based on post-genomic technologies and focuses on societally important diseases, such as immune disorders and infections, cancer and metabolic disorders. CeMM operates in a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society and the arts. The goal of CeMM is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future. CeMM trains a modern blend of biomedical scientists and is located at the campus of the General Hospital and the Medical University of Vienna.
About Medical University of Vienna (MedUni Vienna)
MedUni Vienna is one of the most traditional medical education and research facilities in Europe. With almost 8,000 students, it is currently the largest medical training center in the German-speaking countries. With its 26 university hospitals and two clinical institutes, 12 medical theory centers and numerous highly specialized laboratories, it is also one of Europe's leading research establishments in the biomedical sector.
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