Metabolic Reprogramming Helps to Define Different Metastatic Tropisms in Colorectal Cancer

Abstract

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, in vitro cell-based assays, and in vivo 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 LDLR, CD36, FABP4, SCD, AGPAT1, and FASN, which were also associated with the prognosis of CRC patients. Moreover, CD36 association with lung metastatic tropism of CRC cells was validated in vivo. Altogether, our results suggest that LDLR, CD36, FABP4, SCD, FASN, LPL, and APOA1 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.

A novel prognostic signatures based on metastasis- and immune-related gene pairs for colorectal cancer

“…FABP4 is a novel adipokine that regulates inflammation and angiogenesis and plays a central role in controlling lipolysis and the development of diabetes ( 38 ). In CRC, FABP4 has been reported to be involved in metabolic reprogramming and has been associated with TNM staging, differentiation, and metastatic tropism to the liver or lung ( 39 , 40 ). Nonetheless, the definite mechanism of FABP4 and its relevance to immunity remains to be explored in CRC.…”

In-depth quantitative proteomics analysis revealed C1GALT1 depletion in ECC-1 cells mimics an aggressive endometrial cancer phenotype observed in cancer patients with low C1GALT1 expression

“…For transient ANXA1 silencing, transfection was performed in 6-well plates using the jetPRIME reagent (PolyPlus Transfection) with, alternatively, ON-TARGETplus Human ANXA1 (301) siRNA (J-011161-07-0010; Dharmacon) or control siRNAs (SIC001; Sigma-Aldrich) on shC1GALT1 and SCRAMBLE ECC-1 cells, according to established protocols [ 41 , 42 ]. Briefly, 2.5 × 10 5 cells were transfected with 22 pmol siRNA using 2 µl of JetPRIME Transfection reagent and 100 µl of JetPRIME buffer (PolyPlus Transfection).…”

Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry

“…Another immune cell/macrophage gene widely expressed by human tumor cells (mostly hematopoietic ones but also by some types of solid tumors) is CD47, the activation of which triggers an anti-phagocytic mechanism induced by its ligand SIRPA/CD172a [72,73]. Meanwhile, studies of the tumor microenvironment using markers specific to immune cells revealed that various cancers can express a series of CD markers: CD36 [74][75][76][77], CD58 [78], CD70 [79][80][81][82], CD160 [83,84], CD276 [85], CD320 [86,87], and CD336 [88]. Furthermore, several studies defined cancer stem cell markers [88,89], among which immune cell markers CD90 [88][89][90] and CD166 [91,92] were found to be present in various type of cancers.…”