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Dissertation Dissertation submitted to the Combined Faculty of Natural Sciences and Mathematics of the Ruperto Carola University Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by B.Tech Ashna Alladin born in Mumbai, India Oral Examination : 24th October, 2019 Studying the origins of primary tumours and residual disease in breast cancer Referees : Prof. Dr. Darren Gilmour Prof. Dr. Ana Martin-Villalba To Areeb, now and always ACKNOWLEDGEMENTS 2 Many people and various places have made this thesis and the research behind it pos- sible, and I would like to express my deepest gratitude to each and every one of them. EMBL, for being an inspiring environment, filled with dedicated and enthusiastic scien- tists, many of whom have helped me during my PhD. I am grateful for being accepted to pursue my PhD at EMBL and would like to thank the members of the EIPP Graduate Office (Helke Hillebrand, Monika Lachner, Matija Grgurinovic, Carolina Car- olina Garcia Sabate and Meriam Bezohra). My deepest gratitude is also extended to Reshma Surendran from Human Resources and other members of the administrative departments at EMBL. I owe my heartiest gratitude to Martin Jechlinger for giving me a place in his re- search group in the Cell Biology and Biophysics Unit. I was deeply inspired by his research projects and ideas and am especially grateful for his role in my exposure to innumerable techniques and my overall development as a scientist. My views on scientific method, translational research and group dynamics have been shaped by Martin over the course of the PhD and will guide me for the rest of my life. As far as guidance goes, I want to take this opportunity to express my gratitude to members of my Thesis Advisory Committee: Darren Gilmour, Ana Martin-Villaba and Kiran Raosaheb Patil. I have benefited greatly from their scientific opinions and project discussions during my committee meetings over the years. I would also like to extend my gratitude to Micheal Knop for agreeing to be part of the Defence Committee. No group of people have been more instrumental in helping me achieve my research goals than the past and present members of the Jechlinger Group. Ksenija Radic for being an incredible scientist, a wonderful human being and the best trainer and collabo- rator I have ever had the joy of working with. My deepest gratitude to you Ksenija for helping me every step along the way, from conducting experiments to careful perusal of my thesis. I will always value Alex Shechter's and your contribution to my life and work in Heidelberg. Marta Garcia Montero for teaching me how to grow my first organoid and to sacrifice my first mouse, and for being there for whatever favour, personal and professional, that I needed over the last few years. I would also like to thank Sylwia Gawrzak for her guidance with experiments and valuable advice on all matters of the PhD; Savannah Jade Jackson for her work with the mice and for pensive morning discussions that set the mood for many of my PhD days; Matthew Stephen Boucher for his scientific input and epic humour; Lucas Chaible for being a vital collaborator and a dear friend during his term and of course for his supreme annual BBQs; Miriam Valera-Alberni and Federico Villa for all the science and laughter I shared with them during their short stays. 3 Many of my work hours as a PhD student have been spent at the ALMF core facility at EMBL and so I would like to thank Sabine Reither for all her expertise and help in guiding me along the light sheet microscopy road; Stefan Terjung for his help with all things microscopy; Tobias Rasse for his enthusiasm and scientific input. I would also like to thank the members of the Luxendo family (Monika Loeschinger, Malte Wachsmuth, Soeren Kaufmann) for their dedication towards facilitating all my imag- ing experiments. My greatest thanks to the Centre for Bioimage Analysis (CBA) and Christian Tischer for his brilliance in developing image analysis tools and dedication in helping me decipher umpteen terabytes of data to further my project. I would like to express my gratitude to project collaborators throughout EMBL in- cluding Katharina Zirngibl for her work with the RNASeq data and Jean-Karim Heriche for his computational analysis and scientific input. Numerous other colleagues and core facilities have contributed my research and growth as a scientist { Laboratory Animal Resources (Klaus Schmitt and all the animal technicians); Genomics Core Fa- cility (Vladimir Benes, Jelena Pistolic); Chemical Biology Core Facility (Kerstin Putzker); Centre for Biomolecular Network Analysis (Matt Rogon and Bernd Klaus) and Flow Cytometry Core Facility (Malte Paulsen). I would also like to thank Rocio Sotillo and her lab at the DKFZ for providing invaluable support, especially Charles Yuanyuan Chen for being patient and helpful while I persevered with trying to optimize immunohistochemistry stains. I would also like to thank Robert Prevedel and Jan El- lenberg for their time and suggestions on how to improve my manuscript. No account of my gratitude would be complete without the inclusion of my friends and family who have supported me through all the collateral damage that happens when you pursue science whole-heartedly and with passion. Sanjana Singh has been the best roommate, bridesmaid and chai date to me for the last four years and I would like to thank her for many brilliant scientific discussions and of course, her dardnaak humour. This PhD would be a lot less fun if she hadn't walked into the lab and broken into a song innumerable times. Many thanks also to Sebastian Brosig for translating my thesis summary and for cheering me up in tissue culture when I really needed it. I would also like to thank all my friends and colleagues in the PhD community at EMBL for their help, advice and pursuit of good times. I am grateful to my alma mater VIT University in Vellore, India for allowing me the chance to be inspired by excellent faculty members and supported by the best of friends (Sakshi Dixit Ankita Budhraja, Ashwin Koneru). My special thanks also to Chetna Jain for being the best thing about my hometown and roots. Finally, I would like to thank my husband Areeb Jawed for all he has done for me 4 for the better part of the last decade. Thank you Areeb, for travelling and exploring the world with me, teaching me to relax and appreciate the little things and greatly improving my standards of living and eating. You are a man of brilliance, love and laughter and I am grateful for you every day. More than anyone, I owe my eternal gratitude to my family. My Dad, for his in- advertent lessons on life and the importance of being content. My father made me an independent entity in pursuit of brilliance and I will forever be grateful. My Mom for believing in me, motivating me and fuelling my ambition every day. Nothing and no one can ever compare to the light she brings into my life. My sisters Azra and Zaara for their incredible hearts and unwavering loyalty. Shermin, for all the love, laughter and good living. My grandparents and uncles and aunts and cousins for all the good memories that have made me who I am and given me the courage to pursue my dreams. It really does take a village. 5 SUMMARY 6 Breast cancer is the leading cause of death in women worldwide and these deaths are mostly attributed to metastasis and tumour recurrence following initially successful therapy. Metastasis refers to the development of invasive disease, wherein malignant cells dissociate from primary tumours, infiltrating other organs and tissues to give rise to secondary outgrowths. Previously, metastasis was thought to be initiated in advanced tumours, but breast cancer cellsh with metastatic potential have now been shown to disseminate very early from the primary site via largely unknown mechanisms. These early interactions of tumour cells with their cellular micro-environment and normal neighbours also results in early tumour cell heterogeneity and must therefore be elucidated such that we can prevent metastatic spread in the patient situation and better treat the resulting heterogenous tumours. However, studying tumour initiation is not possible in patients because it happens on a cellular level not detectable by current technology. Tumour recurrence is another major cause of breast cancer related death and is believed to be caused by residual disease cells that survive initial therapy. These are a reservoir of refractory cells that can lay dormant for many years (sometimes decades) before resulting in relapse tumours. They are also difficult to obtain from human patients, since they are very few and cannot be detected easily, and thus their molecular mechanisms have not been fully explored. In addition to the unavailability of human tissue, mouse models of breast cancer also fall short in helping us study early cancer initiation, because they allow oncogenic expression in all cells of the tissue instead of initiating cancer like in the human situation|one neoplastic transformed cell proliferating unchecked in a normal epithelium. To address this issue, we used primary organoids from an inducible mouse model of breast cancer and lentivirally transduced single cells within these organoids to express oncogenes. We further optimized parameters for long term imaging using light sheet microscopy and developed big data analysis pipelines that lead us to discern that single transformed cells had a lower chance at establishing tumorigenic foci, when compared to clusters of cells. Thus, we postulate a proximity-controlled signalling that is imperative to tumour initiation within epithelial tissues using the first ever in vitro stochastic breast tumorigenesis model system.
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