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Spatial metabolomics reveals a reprogramming of lipid metabolism by bacterial colibactin supporting immunosuppressive microenvironment in right-sided colon cancer
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International audience. Introduction: Intratumoral bacteria contribute to tumor heterogeneity through poorly understood mechanisms. It has been established thatpatients with right-sided colon cancer (RCC) exhibit a worse prognosis and differences in their tumor-associated biofilms and lipid metabolism when compared to left-sided colon cancer. However, it remains unclear whether and how the tumor-associated biofilm may influencethe lipid metabolic reprogramming of the tumor microenvironment.Materials and methods: To uncover the impact of Colibactin-producing by Escherichia coli (CoPEC) tumor-associated microenvironmentand bacterial structure, 16S rRNA gene sequencing, metabolomic profiling in situ (7T-MALDI-FTICR), qPCR (to detect the presence ofColibactin) and RNA-sequencing/RNAscope were applied to RCC tumors. To confirm the human data, mouse and human colon carcinomacells (MC38 and HCT116, respectively) were infected with the CoPEC clinical strain (11G5) or with its mutant strain that does not produceColibactin (11G5∆clbQ). Metabolomic in vitro results were confirmed using SpiderMass. Additionally, data were validated using a CoPECinfection on the MC38 mice graft model.Results: By applying metabolomic profiling in situ, the presence of Colibactin-producing Escherichia coli (CoPEC) was identified to establish a high-glycerophospholipid microenvironment within RCC that bears oncogenic mutations in APC. Using spatial approaches, werevealed that bacterial microniches are poorly infiltrated by IFNγ-producing CD8+ T-cells. Notably, CoPEC infection leads to lipid dropletaccumulation in MC38 and HCT116 cells. Interestingly, the aforementioned alterations in lipid metabolism positively correlated with immunomodulatory factors among which the human regenerating family member 3 alpha gene (REG3A). Herein, we revealed that engraftedtumors into Reg3b-deficient mice resulted in similar metabolic adaptation of the tumor together with a significant reduction in tumor growthafter CoPEC infection. These data are supported by a decrease in Lpcat1 expression, a gene involved in the remodeling of glycerophospholipids, observed only in 11G5-infected WT mice. In this same sense, we detected similar changes in the presence of CoPEC in APCmutant-status RCC patients’ tumors and APC-mutated HT-29 cells.Conclusion: This work clarifies how CoPEC may shape tumor heterogeneity through their influence on lipid metabolism and will allow exploration into the mechanisms of CoPEC-mediated lipid reprogramming on the efficacy of antitumoral therapy.
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