Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies
[eng] Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype that lacks targeted therapies, highlighting the need for a deeper understanding of its molecular and cellular mechanisms. Lineage tracing has emerged as a powerful tool to decipher the cellular hierarchies go...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223850 |
| Acesso em linha: | https://hdl.handle.net/2445/223850 http://hdl.handle.net/10803/695559 |
| Access Level: | acceso abierto |
| Palavra-chave: | Carcinogènesi Càncer de mama Metàstasi Citologia Carcinogenesis Breast cancer Metastasis Cytology |
| Resumo: | [eng] Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype that lacks targeted therapies, highlighting the need for a deeper understanding of its molecular and cellular mechanisms. Lineage tracing has emerged as a powerful tool to decipher the cellular hierarchies governing both normal and malignant mammary tissues. Despite significant advancements, knowledge gaps persist regarding how distinct mammary epithelial cell populations contribute to TNBC heterogeneity and progression. By integrating histological, molecular, and lineage-tracing analyses, this thesis provides critical insights into the cellular origins, clonal dynamics, and metastatic potential of different mammary epithelial lineages in preclinical TNBC models. Lineage-tracing experiments reveal that distinct TNBC subtypes arise from specific mammary epithelial cells, with lineage identity and oncogenic plasticity shaping tumor heterogeneity. ERα-negative Notch1-positive luminal cells serve as the cell of origin for TNBCs with a luminal histology resembling luminal B and basal-like human subtypes, while Acta2-positive basal cells generate tumors with basal features mirroring normal- like human tumors. Notably, basal cells exhibit phenotypic plasticity, contributing to the emergence of hybrid tumors that blur conventional subtype boundaries. Clonal expansion studies underscore that the pivotal role of luminal progenitors in luminal B and basal-like TNBC progression. In luminal B tumors, Notch1-positive luminal cells undergo early, robust clonal expansion, followed by a shift toward a more invasive and plastic phenotype in advanced stages, enhancing their metastatic potential. During dissemination, these cells undergo luminal-to-basal transition, enabling them to reconstruct the primary tumor's cellular architecture at distant sites. In advanced stages, Noch1-positive cells are outcompeted by Prom1-positive luminal cells, which exhibit delayed but significant proliferative response, while Acta2-positive basal cells do not contribute to clonal expansion. A similar pattern emerges in basal-like tumors, where Notch1-positive cells, comprising ERα-negative luminal cells and a small subset of basal cells, clonally expand and drive intratumor heterogeneity. These findings highlight the pivotal role of lineage-restricted cellular hierarchies and oncogenic plasticity in shaping TNBC heterogeneity and progression. By identifying distinct cellular origins, their evolving clonal dynamics, and metastatic trajectories, this work offers a mechanistic framework for understanding TNBC evolution. These insights may guide the development of personalized therapeutic strategies tailored to subtype- specific tumor and metastatic origins, while accounting for phenotypic plasticity to prevent tumor initiation and halt dissemination in TNBC patients. |
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