<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells"^^ . "Colorectal cancer (CRC) is one of the main contributors to cancer-related fatality. \r\nPatient survival highly depends on tumour stage at diagnosis, as the 5-year overall survival \r\nrate drops drastically from ~64% for patients diagnosed in stage I–II to 12% for patients\r\ndiagnosed in stage IV. Thus, ~90% of CRC related deaths are associated with metastatic \r\ndisease that does not respond to currently available systemic treatments. Emerging evidence \r\nsuggests that inter- and intra-tumour heterogeneity significantly contributes to cancer \r\nprogression and therapy-resistance. In this PhD thesis, I focus on two main sources of intra-tumour heterogeneity: clonal dynamics and stem cell hierarchy. \r\nDuring CRC progression, the tumour ecosystem is subjected to continuous evolution. \r\nHowever, the patterns of clonal dynamics and their dependence on the surrounding \r\nenvironment are not yet well understood. To investigate this, I used an optical barcoding\r\nsystem (LeGO) in mouse tumour-derived organoids to longitudinally track individual clones in \r\ndifferent environments. My findings revealed a key bottleneck both in vitro and in vivo, \r\nsuggesting that clonal selection plays a major role during CRC progression. Moreover, my \r\nresults indicate that clonal selection is highly influenced by the tumour microenvironment, \r\nwhich critically contributes to tumour heterogeneity and has implications for therapeutic \r\nintervention. \r\nFurthermore, CRC cells are hierarchically organized with cancer stem cells (CSCs) at \r\nthe apex, initiating and fuelling tumour growth. LGR5 has been suggested as the marker for \r\nCSCs in CRC. However, a significant number of CRCs present none of few LGR5+ cells. \r\nLGR5+ CSCs become absent during metastasis initiation and therapy response. Instead, a \r\nfoetal intestinal stem cell program is reactivated. In this thesis, I propose TROP2 as a marker \r\nfor these foetal-like CSCs in CRC and functionally characterized them. My findings suggest a \r\nmutually exclusive distribution of LGR5+ and TROP2+ CSC populations in both, mouse and \r\nhuman CRC, implying that they represent distinct CSC populations. I demonstrated that while \r\nLGR5 marks CSCs in Apcmut CRCs, TROP2 marks CSCs in Apcwt\r\n(WNT-low, serrated) CRCs.\r\nFurthermore, TROP2 expression is associated with advanced tumour stages and poor \r\nprognosis. Here, I showed that, in CRC, TROP2 marks the cells located at the tumour invasive \r\nfront as well as the metastasis-initiating cell. Additionally, TROP2 gain-of-function and loss-of-function experiments revealed its direct, but yet unknown, role in CRC progression. Finally, \r\nTROP2 represents a promising therapeutic target in CRC due to the potent therapeutic activity \r\nof the TROP2 antibody-drug conjugated, Sacituzumab Govitecan (SG). Thus, we have \r\nlaunched a multicentre randomized investigator-initiated trial (phase II/III; NCT06243393) to \r\ntest SG as a 3rd line treatment versus standard-of-care in metastatic CRC patients."^^ . "2025" . . . . . . . "Nuria"^^ . "Vaquero Siguero"^^ . "Nuria Vaquero Siguero"^^ . . . . . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells (PDF)"^^ . . . "PhD Thesis Nuria _final.pdf"^^ . . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Unveiling the Complexity of Colorectal Cancer Heterogeneity. \r\nFrom Clonal Evolution to Cancer Stem Cells (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #36086 \n\nUnveiling the Complexity of Colorectal Cancer Heterogeneity. \nFrom Clonal Evolution to Cancer Stem Cells\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .