Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response

• Published in: Nature communications 2014-11, Vol.5 (1), p.5275-5275, Article 5275
• Main Authors: Houthuijzen, Julia M., Daenen, Laura G. M., Roodhart, Jeanine M. L., Oosterom, Ilse, van Jaarsveld, Marijn T. M., Govaert, Klaas M., Smith, Michelle E., Sadatmand, Sahar J., Rosing, Hilde, Kruse, Fabian, Helms, Bernd J., van Rooijen, Nico, Beijnen, Jos H., Haribabu, Bodduluri, van de Lest, Chris H. A., Voest, Emile E
• Format: Article
• Language: English
• Subjects: 101/58; 13/31; 13/51; 38/77; 631/250/2504/342; 631/337/1427/2566; 631/67/1059/2326; 64/60; Animals; Antineoplastic Agents - therapeutic use; Cancer therapies; Cell cycle; Chemotherapy; Cisplatin - therapeutic use; DNA damage; DNA Damage - physiology; Drug Resistance, Neoplasm - physiology; Fatty acids; Fatty Acids, Unsaturated - physiology; Fatty Acids, Unsaturated - secretion; Humanities and Social Sciences; Kinases; Lysophospholipids - physiology; Lysophospholipids - secretion; Macrophages - physiology; Macrophages - secretion; Male; Mass Spectrometry; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Neoplasms, Experimental - drug therapy; Oncology; Receptors, Leukotriene B4 - physiology; Science; Spleen; Spleen - cytology; Splenectomy; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6275

Host responses to systemic anti-cancer treatment play important roles in the development of anti-cancer drug resistance. Here we show that F4/80 + /CD11b low splenocytes mediate the resistance to DNA-damaging chemotherapeutics induced by two platinum-induced fatty acids (PIFAs), 12-S-keto-5,8,10-heptadecatrienoic acid and 4,7,10,13-hexadecatetraenoic acid (16:4(n−3)) in xenograft mouse models. Splenectomy or depletion of splenic macrophages by liposomal clodronate protects against PIFA-induced chemoresistance. In addition, we find that 12-S-HHT, but not 16:4(n−3), functions via leukotriene B4 receptor 2 (BLT2). Genetic loss or chemical inhibition of BLT2 prevents 12-S-HHT-mediated resistance. Mass spectrometry analysis of conditioned medium derived from PIFA-stimulated splenic macrophages identifies several lysophosphatidylcholines as the resistance-inducing molecules. When comparing cisplatin and PIFA-treated tumours with cisplatin alone treated tumours we found overall less γH2AX, a measure for DNA damage. Taken together, we have identified an intricate network of lysophospholipid signalling by splenic macrophages that induces systemic chemoresistance in vivo via an altered DNA damage response. It is known that mesenchymal stem cells contribute to chemotherapy resistance by secreting polyunsaturated fatty acids. Here the authors show that macrophages in the spleen secrete lysophosphatidylcholines and contribute to chemotherapy resistance by altering the tumour's DNA damage response.