Targeting the mechanism of 5-FU chemoresistance in colorectal cancer by metabolic reprogramming of tumor associated macrophages ; Ciblage du mécanisme de chimiorésistance au 5-FU dans le cancer colorectal par reprogrammation métabolique des macrophages associés à la tumeur

The tumor microenvironment (TME) consists of a highly complex network of stromal and tumoral cells along with other tumor specific factors such as hypoxia, which collectively define the state of the tumor. One of the key players of immune cells within TME are macrophages, hereby called tumor associated macrophages (TAMs). TAMs interfere in the development and progression of tumors either by suppressing it or promoting it through mediating immunosuppressive functions and advocating chemoresistance against chemotherapeutic treatments. In this context, we demonstrated that hypoxia modulates the biology of macrophages and upregulates the expression of dihydropyrimidine dehydrogenase (DPD), which is an enzyme that catabolizes the chemotherapeutic agent 5-fluorouracil (5-FU). This mechanism confers a chemoresistance in human colorectal cancer (CRC). Nevertheless, we showed that this mechanism is controlled at the translational level via the stabilization of HIF-2α. Finally, we proved that only human macrophages display upregulated expression and activity of DPD in CRC tumors where neither colon cancerous cells nor rodents’ macrophages showed any significant DPD levels. Secondarily, to overcome this oxygen-controlled chemoresistance we aimed to develop a strategy to reprogram macrophages metabolically by targeting DPD expression. To do so we used antagonists against the Macrophage Colony Stimulatory Factor Receptor (M-CSF R). Indeed, it was reported that the transcription factor SP1 is activated by M-CSF and possibly control DPD expression. In our study, we report that although all antagonists target M-CSF R pathway via the inhibition its kinases domains, only one antagonist, Edicotinib, specifically targets DPD expression in human macrophages rendering colon cancer cells sensitive to 5-FU. However, we have demonstrated that this effect is mediated independently from SP1 and p-ERK, but related to the ability of Edicotinib to destabilize HIF2α in hypoxia. Nonetheless, we found that Edicotinib significantly reprograms ...