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The Crosstalk between Tumor Stroma Components and ESR1 Mutant Breast Cancer Cells Remodels Tumor Microenvironment and Enhances Tumor Growth and Progression
Author(s) -
Caruso Amanda,
Gelsomino Luca,
Gu Guowei,
Panza Salvatore,
Giordano Cinzia,
Barone Ines,
Malivindi Rocco,
Bonofiglio Daniela,
Catalano Stefania,
Fuqua Suzanne,
Andò Sebastiano
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03453
Subject(s) - tumor microenvironment , biology , cancer research , stroma , metastasis , tumor progression , stromal cell , cancer , estrogen receptor alpha , estrogen receptor , breast cancer , immunology , genetics , tumor cells , immunohistochemistry
Background Cancer is a genetic disease characterized by the progressive accumulation of mutations that randomly occur in key cancer‐related genes such as ESR1 , encoding Estrogen Receptor Alpha (ERα). ESR1 mutations (ESR1m) are rarely detected in primary tumors, but they have been largely found in metastatic breast cancers (BCs). Particularly, mutations in the ligand‐binding domain of ERα may represent one mechanism of clinical acquired resistance after long‐term adjuvant endocrine therapy and are associated with worse clinical outcome. Several studies reported that the complex interactions between the tumor cell niche and its surrounding microenvironment (stroma) are crucial for tumor development and metastasis and influence therapeutic response. The contribution of the tumor stroma in potentiating malignant phenotype of mutated BC cells is one of the most investigated issues. Thus, we evaluated the functional interactions between BC cells expressing the most frequent ESR1m, Y537S, and surrounding stroma and vice versa. Methods As experimental models we used human parental MCF‐7 and Y537S CRISPR BC cells. We ran a microarray analysis to compare genomic profiling of the two BC cell lines and qRT‐PCR to confirm these data. We performed co‐culture experiments employing the most representative tumor stroma components such as the human monocyte cell line, THP‐1, cancer‐associated fibroblasts (CAFs), and pre‐adipocytes derived from a mouse embryo, 3T3L1. We tested the effects of the different tumor stroma components on the behavior of BC cells and vice versa. Results Microarray analysis revealed that mutant BC cells exhibited higher mRNA levels of several genes encoding different mediators of tumor‐stroma interactions compared to parental counterpart. These data have been confirmed with qRT‐PCR assays. Conditioned media (CM) derived from CAFs, macrophages and mature adipocytes increased the growth, migration and invasion of both tested BC cells, even though to a higher extent in the mutant clones. Vice versa, CM‐derived from both BC cells contributed to: i) the dedifferentiation of adipocytes into pre‐adipocytes featured by the reduction in lipid droplets together with the decreased mRNA expression level of adipocyte markers, ii) the higher CAF activation, as revealed by an altered morphology, an increased FAP mRNA expression, and enhanced migratory capabilities, iii) the enhanced recruitment of monocytes displaying tumor associated macrophage markers. It is worth to mention how these events were emphasized in the presence of CM‐derived from mutant cells. Conclusions Our results showed how mutant BC cells educate tumor stroma to further potentiate its own malignant phenotype. In the era of precision medicine, our findings lead to identifying novel drugs able to target stromal components and cancer cells to be both implemented in the therapeutic strategies of BC treatment, particularly in the occurrence of ESR1 mutations.