セミナー情報
2024年9月17日 PM:400 東京都健康長寿医療センター 2階第一会議室
Professor Darren Baker
Professor Department of Pediatric and Adolescent Medicine
Professor Department of Biochemistry and Molecular Biology
Director Transgenic and Gene Knockout Core
Co-Director Paul F. Glenn Center for Biology of Aging Research at Mayo Clinic, Rochester, Minnesota USA
Cancer continues to be an age-related disease that unfortunately shortens the life of far too many people. Despite advances in our mechanistic understanding, the complexity and heterogeneous nature of tumor cells and their microenvironment remains. Our group has focused one age-related mechanism driving disease: cellular senescence. Intrinsically, this protects us from abnormal cells becoming cancerous through induction of a stable cell cycle arrest. However, recent work has demonstrated that senescent cells can promote neoplastic transformation in neighboring cells. In recent work, we have demonstrated that targeting senescent cells delays the formation and progression of lung adenomas in oncogenic Kras mice. Surprisingly, the cells that became senescent to promote neoplasia were the tissue resident macrophages of the lung. Here, we investigate the role of aging in lung tumorigenesis and propose a potential strategy to delay tumor progression and spread by selectively targeting tumor-promoting senescent cells that arise with advancing age to sustain protective antitumor immunity. This talk will highlight some of our more recent understanding for senescent cells in the contribution of driving age-associated tumorigenesis.
2024年7月25日 PM:400 東京都健康長寿医療センター 2階第一会議室
Professor David Bernard
Cellular senescence, Cancer & Aging lab, Cancer Research Center of Lyon, UMR INSERM U1052/CNRS 5286, University of Lyon, France
Cellular senescence is activated in response to developmental signals or stresses during life. It is characterized by a stable proliferation arrest and the acquisition of a senescence-associated secretory phenotype or SASP, composed of numerous factors including pro-inflammatory molecules, proteases and growth factors. Senescent cells can exert beneficial effects when timely regulated (e.g. embryonic development, wound healing) but become deleterious when they accumulate, especially during aging and deleterious exposure (e.g. tobacco, some diets, radiations). The SASP affects the environment of senescent cells by inducing and modulating various phenotypes such as paracrine senescence, immune cell activity, and extracellular matrix deposition and organization, critically impacting various pathophysiological situations, including inflammation, cancer and aging.
We have contributed to the discovery of the important functional roles in regulating cellular senescence of some ions and/or some ion channels in the last years (ref 1-6). In particular, we have identified ITPR2 (Inositol 1,4,5-Trisphosphate Receptor Type 2 or IP3R2) ER-calcium release channel and subsequent mitochondrial calcium accumulation as an important mechanism promoting cellular senescence. Strikingly, Itpr2 KO mice display lower level of senescence, less marks of aging and they live longer in normal aging conditions. ITPR2 channel also facilitate ER-mitochondria calcium transfer by promoting contacts between these two organelles. I will discuss these published results together with some unpublished results on that topic. I will also share unpublished results supporting a critical role of ANGPTL4 secreted factor as a pioneer SASP component, its mechanism of regulation as well as its function in the SASP to promote inflammation and tumor initiation.
参考文献
Lallet-Daher H et al, Cancer Res 2013 73:5253-65
Wiel C et al, Nat Commun 2014 5:3792
Warnier M et al, Aging Cell 2018 17:e12736
Ma X et al, Aging Cell 2018 17:e12831
Ziegler DV et al, Nat Commun 2021 12:720
Czarnecka-Herok J et al, Redox Biol 2024 73:103.