Extended Data Fig. 11: Tumour EVPs suppress liver drug metabolism and enhance chemotoxicity.

a, Schematic illustration of the procedure of drug-metabolizing activity analysis of the PCLS. Substrates of Cytochrome P450 enzymes (including phenacetin, bupropion, tolbutamide, dextromethorphan and midazolam) were added to the media, and their corresponding metabolites (including acetaminophen, hydroxybupropion, 4-hydroxytolbutamide, dextrorphan and 1-hydroxymidazolam) were analyzed by LC-MS/MS. b, Drug-metabolizing activity of the core CYP enzymes in the PCLS sectioned from PBS-injected mice, and B16F10-Tb mice treated with anti-TNF antibody or IgG1 isotype control. n = 5 mice per group. c, Drug-metabolizing activity of Cyp1a2 (left) or Cyp2b10 (right) in the PCLS pre-treated with DMSO control or mathoxsalen (5 µM), or phenobarbital (0.1 mM) for 24 h. n = 3 mice per group. d, Drug-metabolizing activity of the core CYP enzymes in the PCLS sectioned from naïve mice pre-treated with PBS or 10 µg ml⁻¹ of B16F10-CL-EVPs with co-treatment of anti-TNF antibody (20 µg ml⁻¹) or IgG1 isotype (20 µg ml⁻¹) control for 24 h. n = 5 mice per group. e, Schematic illustration of the procedure of chemotoxicity analysis using EVP-educated mice. For melanoma model (top), C57BL/6 mice were intravenously injected with PBS or 10 µg of B16F10-CL-EVPs every other day for 4 weeks, and then intraperitoneally injected with dacarbazine (60 mg kg⁻¹) or 0.9% NaCl together with intravenous injection of PBS or 10 µg of B16F10-CL-EVPs every other day for 4 times. Retroorbital blood of the mice was then collected for complete blood count. For osteosarcoma model (bottom), BALB/c mice were intravenously injected with PBS, 10 µg of osteoblast-EVPs (Ob-EVPs) or K7M2-CL-EVPs every other day for 4 weeks, and then intraperitoneally injected with doxorubicin (1 mg kg⁻¹) or DMSO every 24 h together with intravenous injection of PBS, 10 µg of Ob-EVPs or K7M2-CL-EVPs every other day for 25 days, and mice were then subjected to echocardiography. f, Statistical analysis of the heart rates of PBS-, Ob-EVP- or K7M2-CL-EVP-educated mice after treatment of DMSO or doxorubicin (cumulative dose of 25 mg kg⁻¹). No difference of heart rates was observed in different groups. n = 6 mice for PBS groups and n = 7 mice for K7M2-CL-EVP groups, n = 5 and n = 6 for DMSO and doxorubicin treated Ob-EVP-educated mice, respectively. g, Representative M-mode images of echocardiography for PBS-, Ob-EVP- or K7M2-CL-EVP-educated mice after treatment of DMSO or doxorubicin as described in (e). LVIDd, left ventricular internal dimension at end diastole. LVIDs, left ventricular internal dimension at end systole. EF, ejection fraction. FS, fractional shortening. P values were determined by the one-way ANOVA with post hoc Tukey’s test (b,d), or two-tailed, unpaired Student’s t-test (c), or two-way ANOVA followed with Fisher’s LSD test (f). Data are mean ± s.e.m. NS, not significant. Ob, osteoblast. I.V., intravenours. I.P., intraperitoneal.

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