Lipid signaling in anti-cancer drug resistance

Host responses to systemic anti-cancer treatment play important roles in the development of anti-cancer drug resistance. In this thesis we show that splenic F4/80+/CD11blow macrophages mediate the resistance to DNA-damaging chemotherapeutics induced by two platinum-induced fatty acids (PIFAs), 12-S-keto-5,8,10-heptadecatrienoic acid (KHT) 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 found that 12-S-HHT and 16:4(n-3) function via the leukotriene B4 receptor 2 (BLT2) and G-protein coupled receptor 120 (GPR120) respectively. Genetic loss or chemical inhibition of BLT2 prevents 12-S-HHT-mediated resistance and genetic loss or chemical inhibition of GPR120 prevents 16:4(n-3)-mediated chemoresistance in vivo. Mass spectrometry analysis of conditioned medium derived from PIFA-stimulated splenic macrophages identified several unsaturated lysophosphatidylcholines (LPCs) as the resistance-inducing molecules, of which LPC(24:1) is specifically released in response to 16:4(n-3) stimulation.

When comparing cisplatin and PIFA-treated tumors with cisplatin alone treated tumors we found overall less gH2AX, a measure for DNA damage, and enhanced CHK1 signaling, suggestive of enhanced DNA damage repair. Furthermore, PIFAs are unable to induce chemoresistance in BRCA1-/-;p53-/- mice, a model for loss of homologous recombination-mediated DNA-damage repair.

In addition to MSC-mediated production of 16:4(n-3), certain fish oils and fatty fishes, like mackerel and herring also contain 16:4(n-3) and the concentrations found were within the range known to induce chemoresistance in mice. A healthy volunteer study showed that ingestion of 16:4(n-3)-containing fish oil or fish increased 16:4(n-3) levels in plasma with a peak 4 hours after intake. Interestingly, the fish oils containing relatively high levels of 16:4(n-3) (5-6 mM) were able to increase plasma 16:4(n-3) levels to values known to induce chemoresistance in mice even when they were ingested at the daily recommended dose.

Taken together, we have identified and intricate network of lipid signaling by splenic macrophages that induces systemic chemoresistance in vivo via an altered DNA damage response.