1. SPP1 and TNC are induced by chemotherapy via JNK signaling
SPP1 and TNC are induced by chemotherapy via JNK signaling AGene expression profile of MDA231‐LM2 cells treated with paclitaxel (PAX) for 48 h. Highlighted are examples of JNK signature genes that are induced by PAX treatment.BVenn diagram showing overlap between genes that were significantly (P < 0.05) induced more than 1.5‐fold in response to paclitaxel treatment of MDA231‐LM2 cells and genes that were significantly (P < 0.05) induced in MDA231‐LM2 cells after formation of oncospheres. Significant fold changes were determined by two‐sample empirical Bayer tests with Benjamini–Hochberg correction for multiple testing. PAX, paclitaxel treatment.CGSEA normalized enrichment scores of four independent mammary stem cell signatures that arise in response to paclitaxel treatment of MDA231‐LM2 cells. Signatures a‐d are the same as in Fig 2E. *P < 0.05, ***P <  NS, not significant. P‐values were determined by random permutation test.DImmunofluorescence analysis of p‐c‐Jun expressing cancer cells in lung metastases from mice injected intravenously with MDA231‐LM2 cells and treated with PAX at week 3 post‐injection. Lungs were harvested 72 h after PAX treatment. Cancer cells express GFP as a marker. DAPI was used for nuclear staining. Scale bar, 50 μm.EQuantification of cancer cells expressing p‐c‐Jun (p‐c‐Jun+) in panel (D). Values are mean from three mice ± SEM. Nine metastatic foci were analyzed per mouse. P‐value was determined by a two‐tailed Mann–Whitney test.FWestern blot analyzing phosphorylated JNK (p‐JNK), JNK, phosphorylated c‐Jun (p‐c‐Jun), and c‐Jun in MDA231‐LM2 cells treated with PAX for 48 h. Tubulin was used as a loading control.G, HSPP1 and TNC expression in SUM159‐LM1 cells treated with increasing concentrations of PAX or doxorubicin (DOXO). Values represent the mean of qPCR triplicates ± SD.ISPP1 and TNC expression in SUM159‐LM1 cancer cells treated with 4 μM 5‐fluorouracil or 4 μM methotrexate. Cells were treated for 48 h. Values represent the mean of qPCR triplicates ± SD.JSPP1 and TNC expression in SUM159‐LM1 cells treated with paclitaxel and JNKi. Values represent the mean of qPCR triplicates ± SD. SPP1 and TNC repression by JNKi, P < 0.05 for both vehicle and PAX‐treated cells. P‐values were determined by a Mann–Whitney test. Source data are available online for this figure.
Jacob Insua‐Rodríguez et al. EMBO Mol Med. 2018;emmm
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