resumo
Simple Summary Tumor-associated macrophages (TAM), which constitute the most abundant immune cells in the breast tumor microenvironment (TME), display immune-suppressive functions that promote breast cancer (BC) progression and are associated with poor disease outcomes. Altered metabolism is recognized both as a hallmark of tumor cells and an important determinant of macrophage functional regulation. Hence, characterizing the metabolic crosstalk between tumor cells and TAM represents an attractive approach to discovering new ways of modulating the complex TME towards favorable anti-tumor immunity. The present study elucidates how in vitro generated tumor-educated macrophages (TEM) reprogram their metabolism and phenotype in response to the metabolic conditions imposed by different BC cell subtypes. Several metabolites and metabolic pathways with potential immunoregulatory roles are highlighted, expanding current knowledge on the metabolic-phenotypic axis in TEM. The metabolic crosstalk between tumor cells and tumor-associated macrophages (TAMs) has emerged as a critical contributor to tumor development and progression. In breast cancer (BC), the abundance of immune-suppressive TAMs positively correlates with poor prognosis. However, little is known about how TAMs reprogram their metabolism in the BC microenvironment. In this work, we have assessed the metabolic and phenotypic impact of incubating THP-1-derived macrophages in conditioned media (CM) from two BC cell lines cultured in normoxia/hypoxia: MDA-MB-231 cells (highly metastatic, triple-negative BC), and MCF-7 cells (less aggressive, luminal BC). The resulting tumor-educated macrophages (TEM) displayed prominent differences in their metabolic activity and composition, compared to control cells (M0), as assessed by exo- and endometabolomics. In particular, TEM turned to the utilization of extracellular pyruvate, alanine, and branched chain keto acids (BCKA), while exhibiting alterations in metabolites associated with several intracellular pathways, including polyamines catabolism (MDA-TEM), collagen degradation (mainly MCF-TEM), adenosine accumulation (mainly MDA-TEM) and lipid metabolism. Interestingly, following a second-stage incubation in fresh RPMI medium, TEM still displayed several metabolic differences compared to M0, indicating persistent reprogramming. Overall, this work provided new insights into the metabolic plasticity of TEM, revealing potentially important nutritional exchanges and immunoregulatory metabolites in the BC TME.
palavras-chave
GLIOBLASTOMA CELLS; PHENOTYPE; INSIGHTS; CITRATE
categoria
Oncology
autores
Dias, AS; Almeida, CR; Helguero, LA; Duarte, IF
nossos autores
Iola Melissa Fernandes Duarte
Investigador PrincipalProjectos
CICECO - Aveiro Institute of Materials (UIDB/50011/2020)
CICECO - Aveiro Institute of Materials (UIDP/50011/2020)
Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)
agradecimentos
This work was developed in the scope of the projects iBiMED-Institute of Biomedicine (UIDB/04501/2020 and CENTRO-01-0246-FEDER-000018) and CICECO-Aveiro Institute of Materials (UIDB/50011/2020, UIDP/50011/2020 and LA/P/0006/2020), financed by national funds through the FCT/MEC (PIDDAC). A.S.D. acknowledges the financial support from FCT through a PhD grant (Ref. SFRH/BD/140322/2018). Support from "Liga Portuguesa Contra o Cancro" is also acknowledged. The NMR spectrometer is part of the National NMR Network (PTNMR), partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI, and PORL and FCT through PIDDAC).