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

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.

Animal model considerations for chordoma research: reproducing the tumor microenvironment in vivo with humanized mice

“…We can learn from these examples that chordoma can evade the immune system by evading the recognition via antigen restriction by the TIL and marrow-infiltrating lymphocytes (MIL), or by directly interacting with the immune system and inhibiting it or by causing T cell exhaustion, as happens in many other cancers ( 142 ). Moreover, not only the TIME can regulate immune escape, it has been suggested in other cancers that can also promote distant metastasis and the acquired resistance to chemotherapy and radiotherapy ( 143 – 145 ). CAR-modified T cells that could inhibit the molecule B7-H3 are also being explored in chordoma ( 146 ).…”

Development of a customizable mouse backbone spectral flow cytometry panel to delineate immune cell populations in normal and tumor tissues

“…Therefore, myeloid and lymphoid cells can have both protumor and antitumor effects, making it essential to understand the relative contribution of each immune cell subset to the TME and the infiltrated organs, or the observed phenotype and/or response to immunotherapy ( 14 – 18 ). Yet, studying immune cell populations in the TME can pose challenges due to its dynamic nature, the unique characteristics of the affected organ or tissue, and the tumor-specific recruitment of myeloid and lymphoid populations ( 11 , 19 , 20 ).…”

A Comprehensive Model to Differentiate Spontaneous, Drug-induced, and CSCs-related Drug Resistance

“…However, its effectiveness is limited by tumor resistance to drug: 90% of chemotherapy failure is related to drug resistance [2]. Microenvironmental and molecular factors play a major role in most drug resistance development [2,3]. For instance, hypoxia, as a microenvironmental factor, is crucial in the efficacy of certain anticancer drugs and radiation therapy [4,5].…”