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This dissertation uses organoid scalability with single-cell omics to chart CSC polarisation, identify analysis bottlenecks, and characterize transcriptional landscapes.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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core research problem addressed in the thesis?","Question",{"text":63,"@type":64},"The thesis addresses how intrinsic and stromal cues jointly polarise colonic cancer stem cell (CSC) states in colorectal cancer, a process that remains incompletely understood.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does the thesis study CSC polarisation?",{"text":68,"@type":64},"It computationally analyzes heterocellular colorectal cancer organoid systems using single-cell omic data to resolve complex interaction and polarisation processes.",{"name":70,"@type":61,"acceptedAnswer":71},"What methods or tools are developed to enable the research?",{"text":72,"@type":64},"The work designs the CyGNAL pipeline and a cell-state classifier, introduces a valley-ridge (VR) score for visualizing differentiation landscapes, and proposes directed knowledge graph-based communication 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dissertation submitted in partial fulfillment of the requirements for the degree of  \nDoctor of Philosophy  \nof  \nUniversity College London.  \nDepartment of Oncology  \nUniversity College London  \nSeptember 26, 2023  \n2  \nI, Ferran Cardoso Rodriguez, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the work.  \nAbstract 3  \nAbstract  \nColonic epithelia is regulated by cell-intrinsic and cell-extrinsic cues, both in homeostatic tissues and colorectal cancer (CRC), where the tumour microenvironment closely interacts with mutated epithelia. Our understanding on how these cues polarise colonic stem cell (CSC) states remains incomplete. Indeed, charting the interaction between intrinsic and stromal cues requires a systematic study yet to be found in the literature.  \nIn this work I present my efforts towards computationally studying colonic stem cell polarisation at single-cell resolution. Leveraging the scalability of organoid models, my colleagues and I dissected the heterocellular CRC organoid system presented in Qin & Cardoso Rodriguez et al. [1] using single-cell omic analyses, resolving complex interaction and polarisation processes.  \nFirst, I identified bottlenecks in common mass cytometry (MC) analysis workflows benefiting from either increased accessibility or automation; designing the CyGNAL pipeline and developing a cell-state classifier to tackle these points respectively. I then used single-cell RNA sequencing (scRNA-seq) data to reveal a shared landscape of CSC polarisation; wherein stromal cues polarise the epithelia towards slow-cycling revival CSC (revCSC) and oncogenic mutations trap cells ina hyper-proliferative CSC (proCSC) state. I then developed a method to visualise single-cell differentation using a novel valley-ridge (VR) score, which can generate data-driven Waddington-like landscapes that recapitulate differentiation dynamics of the colonic epithelia. Finally, I explored an approach for holistic inter-and intracellular communication analysis by incorporating literature information as a directed knowledge graph (KG), showing that low-dimensional representations of the graph retain biological information and that projected cellular profiles recapitulate their transcriptomes.  \nThese results reveal a polarisation landscape where CRC epithelia is trapped ina proCSC state refractory to stromal cues, and broadly show the importance of joint collaborative wet-and dry-lab work; central towards targeting gaps in the method space and generating a comprehensive analysis of heterocellular signalling in cancer.  \nImpact Statement  \nBy investigating the intricate interplay between intrinsic and extrinsic cues regulating CSC fates, the research and work presented in this thesis sheds new light on the landscape of colonic epithelia polarisation and offers insights into potential therapeutic strategies.  \nFurthering the spirit of shared scientific knowledge and collaborative research, data and code used to generate the analyses in Qin & Cardoso Rodriguez et al. have been made public in various repositories. Furthermore, tools and outputs developed during my project and presented in this thesis have also been made publicly available; either as part of peer-reviewed publications such as CyGNAL in Sufi & Qin et al. [2], as software packages like pyKrack (Appendix A, ferranc96 . [github. io/pyKrack](github. io/pyKrack)), or in the form of publicly accessible GitHub repositories.  \nTools like CyGNAL and the VR landscapes have already impacted research in my lab, facilitating routine MC analyses and empowering Ramos Zapatero & Tong et al. [3] during the ongoing revision process. Furthermore, general knowledge acquired before and during my PhD has been shared with colleagues; either in the form of scientific discussio","cbCaiaklhE34c49m","https://ap.wps.com/l/cbCaiaklhE34c49m","pdf",26783795,218,"English","# Abstract\n## Impact Statement\n## Further Public Availability of Tools and Outputs\n## Acknowledgements","[{\"question\":\"What is the core research problem addressed in the thesis?\",\"answer\":\"The thesis addresses how intrinsic and stromal cues jointly polarise colonic cancer stem cell (CSC) states in colorectal cancer, a process that remains incompletely understood.\"},{\"question\":\"How does the thesis study CSC polarisation?\",\"answer\":\"It computationally analyzes heterocellular colorectal cancer organoid systems using single-cell omic data to resolve complex interaction and polarisation processes.\"},{\"question\":\"What methods or tools are developed to enable the research?\",\"answer\":\"The work designs the CyGNAL pipeline and a cell-state classifier, introduces a valley-ridge (VR) score for visualizing differentiation landscapes, and proposes directed knowledge graph-based communication analysis.\"}]","Charting the Single-Cell Landscape of Colorectal Cancer Stem Cell Polarisation | PDF",1791026108,549]