Impact of intratumoral EMT heterogeneity on breast cancer progression

• Autores: Raúl Jiménez Castaño
• Directores de la Tesis: María Ángela Nieto Toledano (dir. tes.), KHALIL KASS YOUSSEF (codir. tes.), Juan Galcerán Saéz (tut. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2026
• Idioma: inglés
• Tribunal Calificador de la Tesis: Héctor Peinado (presid.), José Vicente Sánchez Mut (secret.), Direna Alonso Curbelo (voc.)
• Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
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• Resumen

  • Despite notable progress in cancer therapies that have prolonged median survival, metastatic relapse remains the leading cause of cancer-related mortality. Metastasis is a complex, multistep process only activated in a minority of cancer cells. Its timing is markedly heterogeneous, some patients present with metastases at diagnosis, whereas in others, secondary lesions emerge years after initial treatment. Recent discoveries have advanced our understanding of the determinants of metastatic competence. Nonetheless, most studies emphasize the role of the metastatic microenvironment, leaving the contribution of cancer cell-intrinsic states upon arrival largely unexplored.

    In this thesis, through the analysis of human breast cancer samples, preclinical in vivo models, and culture systems, we demonstrate that (i) cancer cells depart the primary tumor with a pre-established metastatic potential, and (ii) metastatic outgrowths recapitulate the epithelial–mesenchymal transition (EMT) hierarchies observed in the primary tumor.

    Specifically, the integration of spatial and single-cell transcriptomics plus chromatin accessibility data reveals that the plasticity factor Prrx1 is a central regulator of metastatic potential. Beyond its established role in promoting invasion, Prrx1 suppresses proliferation by modulating the expression of cell cycle regulators (Ccnd1/2, Cdkn2a/b/c) and induces a dormancy program through targets such as Gas6, Mme, and Ogn. Importantly, intermediate levels of Prrx1 achieve a critical balance between invasiveness and proliferation, resulting in a hormetic (non-linear) relationship between its expression and metastatic burden. As such, Prrx1 expression within the primary tumor emerges as a determinant of metastatic competence, and its intratumoral heterogeneity provides a framework to understand why some invasive cancer cells enter dormancy while others continue to grow at distant tissues.

    In addition, analysis of the EMT status across the primary tumor, circulating tumor cells, and metastatic lesions in spontaneous metastatic breast cancer mouse models confirmed the EMT origin of disseminating cells and revealed their high plasticity potential. Despite exhibiting an active, embryonic-like EMT program, metastatic cells retain the ability to recreate the distribution between embryonic and adult-like EMT programs, observed in the primary tumor.

    Finally, we show that the combined expression of invasion and proliferation gene signatures enables robust prognostic stratification of breast cancer patients, underscoring the clinical significance of this phenotypic axis.