Identifying and Evaluating Mechanisms of Drug Resistance in Cancer
Martin, Kelly A
Loots, Gabriela G
Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular alterations that contribute to drug resistance in advanced urothelial carcinoma. Transcriptomic profiling of passage 4 (P4) bladder cancer xenograft tumors from two PDX lines was performed by RNA-sequencing analysis, before and after a 21-day cisplatin/gemcitabine drug treatment regimen. Further analysis identified methionine adenosyltransferase 1a (MAT1A) to be one of the top enriched genes in a statistically significant fashion following chemotherapy treatment in both unique bladder cancer xenograft lines. Here, we have shown and further validated that methionine adenosyltransferase 1a (MAT1A) plays an important role in contributing to tumor progression and response to drug therapy. We implicate MAT1A directly in modulating cell survival in the presence of drug therapy through transcriptional changes and altered cell proliferation. Additionally, our findings also suggest that NNMT may also play a role in promoting cell response to chemotherapy and an aggressive cancer phenotype.In addition to drug resistance, metastasis is another significant clinical problem that limits the efficacy of anticancer therapy. Here, we have also developed an ultrasensitive assay to label, track and quantify rare events of cancer cell metastasis through incorporating radioactive carbon-14 into DNA of new cells. Together, work shown here contributes to our understanding of cancer biology and has provided novel opportunities and methodologies for both the study of cancer metastasis and identification of new targets for therapeutic intervention.
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