Tumor ecology and the paradox of clean margins in multicentric breast cancer - an exploratory organoid-based functional study

Sep 22, 2026

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The gene-centric paradigm has advanced mechanistic insight into cancer, yet it cannot fully explain the clinical heterogeneity seen in complex cases. An eco-evolutionary framework views tumors as dynamic systems shaped by interactions among malignant clones, stromal components, immune populations and the surrounding microenvironment. In multicentric/multifocal breast cancer, patient-derived organoids from histologically tumor-free margins can acquire stem-like and basal-like traits in defined culture conditions, while organoids from primary regions tend to show more differentiated phenotypes.

LanguageEnglish

CategoryResearch & Report

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Pages14

Reading Time35 min

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Abstract

Introduction

Eco-evolutionary framework and tumor ecosystems

Tumor ecology parallels natural ecosystem principles

Multicentric/multifocal breast cancer context

Martínez-Illescas etal. Breast Cancer Research (2026) 28:123 Breast Cancer Research [https://doi.org/10.1186/s13058-026-02301-z](https://doi.org/10.1186/s13058-026-02301-z) PERSPECTIVE Open Access Tumor ecology and the paradox of clean margins in multicentric breast cancer: an exploratory organoid-based functional study Nuria G. Martínez-Illescas 1,2, Estrella Martín-Zapater1, Camila Quezada-Gutiérrez1, Laura Yébenes3, Ana Payo-Payo4, Laura Frías-Aldeguer5 and María Salazar-Roa1,2* Abstract The gene-centric view of cancer has provided important mechanistic insights, but does not fully account for the clinical heterogeneity observed in complex cases. An eco-evolutionary framework instead conceptualizes tumors as dynamic systems shaped by interactions among malignant clones, stromal components, immune populationsand the surrounding microenvironment. Multicentric/multifocal breast cancer (MMBC) provides a relevant context in which to explore this biological complexity. Using patient-derived organoids, we observed that organoids derived from histologically tumor-free margins can display stem-like and basal-like features under defined culture conditions, whereas those from primary tumor regions may exhibit more differentiated phenotypes. These observations suggest that histological margin status alone may not fully capture the functional heterogeneity of peritumoral tissue. Our findings support the hypothesis that biological influences within the margin region may contribute to shaping cellular phenotypes beyond the presence of overt malignant cells. Overall, this study highlights the potential value of integrating organoid-based functional approaches with eco-evolutionary concepts to further investigate the biological landscape of the peritumoral field in MMBC. Keywords Multicentric/multifocal breast cancer, Tumor ecology, Tumor heterogeneity, Margin biology, Cancer organoids, Functional research tools, Eco-evolutionary modelling *Correspondence: María Salazar-Roa [masala08@ucm.es](masala08@ucm.es) 1Cancer STEM Laboratory, Department Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University (UCM), Madrid, Spain 2Breast and Gynecologic Cancer Group, Research Institute i+12, Madrid, Spain 3Anatomical Pathology Unit, Hospital La Paz, Madrid, Spain 4Animal Ecology Laboratory, Department Biodiversity, Ecology and Evolution, Faculty of Biological Sciences, Complutense University (UCM), Madrid, Spain 5Mammary Pathology Unit, Hospital La Paz, Madrid, Spain Introduction Over the last several decades, the study of cancer has been dominated by a gene-centric paradigm. Catalogs of driver mutations, oncogenic signaling pathways, and molecular subtypes have advanced our understanding of tumor biology and inspired the development of targeted therapies and precision medicine approaches [1]. These molecularly guided strategies have extended survival in many cancer types, including breast cancer [2]. Despite these achievements, major clinical challenges remain unresolved. Local recurrence, therapeutic resistance and heterogeneous treatment responses still undermine durable cures, and such phenomena are not fully explained by genetic alterations alone. Increasingly, © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If m

FAQs

Why does a gene-centric view not fully explain breast cancer heterogeneity?

Genetic alterations alone do not account for local recurrence, therapeutic resistance and heterogeneous treatment responses observed clinically.

What does the study suggest about tumor-free histological margins?

Organoids derived from histologically tumor-free margins can still show stem-like and basal-like features under defined culture conditions, indicating functional heterogeneity beyond visible malignant cells.

How does the eco-evolutionary perspective relate to treatment outcomes?

Therapies act as perturbations that reshape selective pressures, allowing tumor ecosystems to reorganize and favor resistant phenotypes or supportive niches, potentially on clinically relevant timescales.

Sep 22, 2026

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