Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response.
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.
Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Julia M
JM
Houthuijzen
Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Laura G M
LG
Daenen
Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Jeanine M L
JM
Roodhart
Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Ilse
I
Oosterom
Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Marijn T M
MT
van Jaarsveld
Department of Surgery, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Klaas M
KM
Govaert
Department of Microbiology and Immunology, University of Louisville, KY 40292, USA.
Michelle E
ME
Smith
Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Sahar J
SJ
Sadatmand
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Hilde
H
Rosing
Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Fabian
F
Kruse
Department of Biochemistry and Cell Biology. Faculty of Veterinary Medicine, Utrecht University, 3584 CX Utrecht, The Netherlands.
Bernd J
BJ
Helms
Department of Molecular Cell Biology, Faculty of Medicine, VUMC, 1081 BT Amsterdam, The Netherlands.
Nico
N
van Rooijen
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Jos H
JH
Beijnen
Department of Microbiology and Immunology, University of Louisville, KY 40292, USA.
Bodduluri
B
Haribabu
Department of Biochemistry and Cell Biology. Faculty of Veterinary Medicine, Utrecht University, 3584 CX Utrecht, The Netherlands.
Chris H A
CH
van de Lest
Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Emile E
EE
Voest
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D004249:DNA Damage / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism* / Q000502:physiology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy; D018102:Receptors, Leukotriene B4 / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013156:Splenectomy
D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; C412867:Ltb4r2 protein, mouse; D008246:Lysophospholipids; D018102:Receptors, Leukotriene B4; C562199:hexadeca-4,7,10,13-tetraenoic acid; C052515:12-keto-5,8,10-heptadecatrienoic acid; D002945:Cisplatin