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

Julia M. Houthuijzen, Laura G. M. Daenen, Jeanine M. L. Roodhart, Ilse Oosterom, Marijn T. M. van Jaarsveld, Klaas M. Govaert, Michelle E. Smith, Sahar J. Sadatmand, Hilde Rosing, Fabian Kruse, Bernd J. Helms, Nico van Rooijen, Jos H. Beijnen, Bodduluri Haribabu, Chris H. A. van de Lest and Emile E Voest ()
Additional contact information
Julia M. Houthuijzen: The Netherlands Cancer Institute
Laura G. M. Daenen: University Medical Center Utrecht
Jeanine M. L. Roodhart: University Medical Center Utrecht
Ilse Oosterom: University Medical Center Utrecht
Marijn T. M. van Jaarsveld: The Netherlands Cancer Institute
Klaas M. Govaert: University Medical Center Utrecht
Michelle E. Smith: University of Louisville, KY 40292, USA
Sahar J. Sadatmand: The Netherlands Cancer Institute
Hilde Rosing: The Netherlands Cancer Institute/Slotervaart Hospital
Fabian Kruse: University Medical Center Utrecht
Bernd J. Helms: Utrecht University
Nico van Rooijen: Faculty of Medicine, VUMC
Jos H. Beijnen: The Netherlands Cancer Institute/Slotervaart Hospital
Bodduluri Haribabu: University of Louisville, KY 40292, USA
Chris H. A. van de Lest: Utrecht University
Emile E Voest: The Netherlands Cancer Institute

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract Host responses to systemic anti-cancer treatment play important roles in the development of anti-cancer drug resistance. Here we show that F4/80+/CD11blow 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.

Date: 2014
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DOI: 10.1038/ncomms6275

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