The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity

Vincenzo Salemme; Giorgia Centonze; Lidia Avalle; Dora Natalini; Alessio Piccolantonio; Pietro Arina; Alessandro Morellato; Ugo Ala; Daniela Taverna; Emilia Turco; Paola Defilippi

doi:10.3389/fonc.2023.1170264

The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity

Front Oncol. 2023 May 17:13:1170264. doi: 10.3389/fonc.2023.1170264. eCollection 2023.

Authors

Vincenzo Salemme^{1

2}, Giorgia Centonze^{1

2}, Lidia Avalle^{1

2}, Dora Natalini^{1

2}, Alessio Piccolantonio^{1

2}, Pietro Arina³, Alessandro Morellato^{1

2}, Ugo Ala⁴, Daniela Taverna^{1

2}, Emilia Turco¹, Paola Defilippi^{1

2}

Affiliations

¹ Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
² Molecular Biotechnology Center (MBC) "Guido Tarone", Turin, Italy.
³ UCL, Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom.
⁴ Department of Veterinary Sciences, University of Turin, Grugliasco, TO, Italy.

Abstract

Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, and this heterogeneity is a crucial determinant of malignant progression and response to treatments. In addition to genetic diversity and plasticity of cancer cells, the tumor microenvironment contributes to tumor heterogeneity shaping the physical and biological surroundings of the tumor. The activity of certain types of immune, endothelial or mesenchymal cells in the microenvironment can change the effectiveness of cancer therapies via a plethora of different mechanisms. Therefore, deciphering the interactions between the distinct cell types, their spatial organization and their specific contribution to tumor growth and drug sensitivity is still a major challenge. Dissecting intra-tumor heterogeneity is currently an urgent need to better define breast cancer biology and to develop therapeutic strategies targeting the microenvironment as helpful tools for combined and personalized treatment. In this review, we analyze the mechanisms by which the tumor microenvironment affects the characteristics of tumor heterogeneity that ultimately result in drug resistance, and we outline state of the art preclinical models and emerging technologies that will be instrumental in unraveling the impact of the tumor microenvironment on resistance to therapies.

Keywords: breast cancer; cancer heterogenicity; drug resistance; molecular mechanisms; tumor microenvironment.

Publication types

Review

Grants and funding

The research leading to these results has received funding from AIRC under IG 2017 – ID. 20107 project and IG 2022 - ID. 27353 project – P.I. PD. This work was also supported by: Fondazione CRT 2020.1798, RILO University of Torino (IG 11904, IG 15538), Ministero della Salute (RF-2021-12371961) to PD, and PNRR M4C2-Investimento 1.4-CN00000041 “Finanziato dall’Unione Europea-NextGenerationEU” to PD and DT.