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...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223850 |
| Acceso en línea: | https://hdl.handle.net/2445/223850 http://hdl.handle.net/10803/695559 |
| Access Level: | acceso abierto |
| Palabra clave: | Carcinogènesi Càncer de mama Metàstasi Citologia Carcinogenesis Breast cancer Metastasis Cytology |
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Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| title |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| spellingShingle |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies Vinuesa Pitarch, Elena Carcinogènesi Càncer de mama Metàstasi Citologia Carcinogenesis Breast cancer Metastasis Cytology |
| title_short |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| title_full |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| title_fullStr |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| title_full_unstemmed |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| title_sort |
Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studies |
| dc.creator.none.fl_str_mv |
Vinuesa Pitarch, Elena |
| author |
Vinuesa Pitarch, Elena |
| author_facet |
Vinuesa Pitarch, Elena |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Rodilla Benito, Verónica Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut |
| dc.subject.none.fl_str_mv |
Carcinogènesi Càncer de mama Metàstasi Citologia Carcinogenesis Breast cancer Metastasis Cytology |
| topic |
Carcinogènesi Càncer de mama Metàstasi Citologia Carcinogenesis Breast cancer Metastasis Cytology |
| description |
[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. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
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publishedVersion |
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https://hdl.handle.net/2445/223850 http://hdl.handle.net/10803/695559 |
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https://hdl.handle.net/2445/223850 http://hdl.handle.net/10803/695559 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
(c) Vinuesa Pitarch, Elena, 2025 info:eu-repo/semantics/openAccess |
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(c) Vinuesa Pitarch, Elena, 2025 |
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openAccess |
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application/pdf |
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Universitat de Barcelona |
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Universitat de Barcelona |
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Tesis Doctorals - Facultat - Medicina i Ciències de la Salut reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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1869405474503262208 |
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Exploring the cellular origins and clonal dynamics of preclinical triple-negative breast cancer models through lineage tracing studiesVinuesa Pitarch, ElenaCarcinogènesiCàncer de mamaMetàstasiCitologiaCarcinogenesisBreast cancerMetastasisCytology[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.[cat] El càncer de mama triple negatiu (TNBC) és un subtipus altament agressiu i heterogeni que manca de teràpies dirigides, fet que ressalta la necessitat de comprendre millor els seus mecanismes moleculars i cel·lulars. El rastreig de llinatge (lineage tracing) s'ha consolidat com una eina poderosa per desxifrar les jerarquies cel·lulars que governen tant els teixits mamaris normals com els malignes. Malgrat avenços significatius, persisteixen llacunes sobre com les diferents poblacions de cèl·lules epitelials mamàries contribueixen a la heterogeneïtat i progressió del TNBC. Integrant anàlisis histològiques, moleculars i de lineage tracing, aquesta tesi proporciona coneixements clau sobre els orígens cel·lulars, la dinàmica clonal i el potencial metastàtic de diferents llinatges epitelials mamaris en models preclínics de TNBC. Els experiments de lineage tracing revelen que diferents subtipus de TNBC sorgeixen de cèl·lules epitelials mamàries específiques, amb la identitat de llinatge i la plasticitat oncogènica modelant la heterogeneïtat tumoral. Les cèl·lules luminals ERα-negatives Notch1-positives serveixen com a cèl·lules d'origen per als TNBC amb una histologia luminal que s'assemblen als subtipus luminal B i basal-like humans, mentre que les cèl·lules basals Acta2-positives generen tumors amb característiques basals que imiten els tumors normal-like humans. Cal destacar que les cèl·lules basals mostren plasticitat fenotípica, contribuint a l'emergència de tumors híbrids que desdibuixen les fronteres convencionals entre subtipus. Els estudis d'expansió clonal destaquen el paper fonamental dels progenitors luminals en la progressió dels TNBC luminal B i basal-like. En els tumors luminal B, les cèl·lules luminals Notch1-positives experimenten una expansió clonal primerenca i robusta, seguida d'un canvi cap a un fenotip més invasiu i plàstic en etapes avançades, augmentant així el seu potencial metastàtic. Durant la disseminació, aquestes cèl·lules experimenten una transició luminal-a-basal, la qual els permet reconstruir l'arquitectura cel·lular del tumor primari en llocs distants. En estadis avançats, les cèl·lules Notch1-positives són desplaçades per les cèl·lules luminals Prom1-positives, que mostren una resposta proliferativa retardada però significativa, mentre que les cèl·lules basals Acta2-positives no contribueixen a l'expansió clonal. Un patró similar s'observa en els tumors basal-like, on les cèl·lules Notch1-positives, que inclouen cèl·lules luminals ERα-negatives i un petit subconjunt de cèl·lules basals, s'expandeixen clonalment i impulsen la heterogeneïtat intratumoral. Aquests descobriments ressalten el paper fonamental de les jerarquies cel·lulars restringides al llinatge i la plasticitat oncogènica en el modelatge de la heterogeneïtat i progressió del TNBC. En identificar orígens cel·lulars específics, la seva dinàmica clonal evolutiva i les trajectòries metastàtiques, aquest treball ofereix un marc mecanístic per comprendre l'evolució del TNBC. Aquests coneixements podrien guiar el desenvolupament d'estratègies terapèutiques personalitzades, adaptades a l’origen tumoral i metastàtic específic de cada subtipus, tenint en compte la plasticitat fenotípica per prevenir la iniciació tumoral i aturar la disseminació en pacients amb TNBC.Universitat de BarcelonaRodilla Benito, VerónicaUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut2025info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/223850http://hdl.handle.net/10803/695559Tesis Doctorals - Facultat - Medicina i Ciències de la Salutreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Vinuesa Pitarch, Elena, 2025info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2238502026-05-27T06:46:51Z |
| score |
15,81155 |