Myeloma-Associated Macrophages Protect Tumor Cells By Reprogramming of Lipid Metabolism through SREBP1

Introduction: With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has significantly improved. However,MM remains incurable due to drug resistance. Hence, there is an urgent need to develop novel therapeutic targets and agents. Lipid metabolism disorder is one of the important characteristics of drug-resistant myeloma cells. While statins can induce drug resistance by regulating lipid metabolism in MM and can also increase MM cells' sensitivity to chemotherapy, the key factors in MM cells' lipid metabolism remain u unrevealed. Myeloma-associated macrophages (mMΦs) are prominent components in the bone marrow of MM patients and induce drug resistance by protecting tumor cells from chemotherapy-induced apoptosis. However, no studies have investigated whether mMΦs regulate lipid metabolism of myeloma cells. Therefore, our study aims to explore the role of mMΦs in MM lipid metabolism, and further understand the molecular mechanisms involved.

Results: Our study found that the fatty acid (FA) in MM cells increased significantly after cocultured with mMφs detected by flow cytometry, and FA could protect MM cells from apoptosis induced by bortezomib, which suggested that mMφs could probably induce MM drug resistance through lipid metabolism regulation. To explore the molecular mechanisms in the process, RNA sequencing was used to detect the differential genes expression involved in lipid metabolism cocultured with or without mMφs. We further found that expression of SREBP1, a key transcription factor of FA synthesis increased significantly in MM cells after cocultured with mMφs. And the result was validated by qPCR and western blot. Importantly, we found that SREBP1 in CD138+ plasma cells of relapsed myeloma patients was significantly higher than that of newly diagnosed patients by double immunofluorescence techniques.

Conclusion: Our study found that mMφs may promote FA synthesis in MM cells through regulating SREBP1, and ultimately induce MM drug resistance, which suggested that lipid metabolism pathway is a possible target for MM treatment.

No relevant conflicts of interest to declare.