AUTHOR=Montero-Calle Ana , Gómez de Cedrón Marta , Quijada-Freire Adriana , Solís-Fernández Guillermo , López-Alonso Victoria , Espinosa-Salinas Isabel , Peláez-García Alberto , Fernández-Aceñero María Jesús , Ramírez de Molina Ana , Barderas Rodrigo 

TITLE=Metabolic Reprogramming Helps to Define Different Metastatic Tropisms in Colorectal Cancer

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.903033

DOI=10.3389/fonc.2022.903033

ISSN=2234-943X

ABSTRACT=<p>Approximately 25% of colorectal cancer (CRC) patients experience systemic metastases, with the most frequent target organs being the liver and lung. Metabolic reprogramming has been recognized as one of the hallmarks of cancer. Here, metabolic and functional differences between two CRC cells with different metastatic organotropisms (metastatic KM12SM CRC cells to the liver and KM12L4a to the lung when injected in the spleen and in the tail vein of mice) were analysed in comparison to their parental non-metastatic isogenic KM12C cells, for a subsequent investigation of identified metabolic targets in CRC patients. Meta-analysis from proteomic and transcriptomic data deposited in databases, qPCR, WB, <italic>in vitro</italic> cell-based assays, and <italic>in vivo</italic> experiments were used to survey for metabolic alterations contributing to their different organotropism and for the subsequent analysis of identified metabolic markers in CRC patients. Although no changes in cell proliferation were observed between metastatic cells, KM12SM cells were highly dependent on oxidative phosphorylation at mitochondria, whereas KM12L4a cells were characterized by being more energetically efficient with lower basal respiration levels and a better redox management. Lipid metabolism-related targets were found altered in both cell lines, including <italic>LDLR</italic>, <italic>CD36</italic>, <italic>FABP4</italic>, <italic>SCD</italic>, <italic>AGPAT1</italic>, and <italic>FASN</italic>, which were also associated with the prognosis of CRC patients. Moreover, CD36 association with lung metastatic tropism of CRC cells was validated <italic>in vivo.</italic> Altogether, our results suggest that <italic>LDLR</italic>, <italic>CD36</italic>, <italic>FABP4</italic>, <italic>SCD</italic>, <italic>FASN</italic>, <italic>LPL</italic>, and <italic>APOA1</italic> metabolic targets are associated with CRC metastatic tropism to the liver or lung. These features exemplify specific metabolic adaptations for invasive cancer cells which stem at the primary tumour.</p>