Application of single cell transcriptome analysis to suggest a personalized anticancer therapeutic strategy Da Eun Jeong1,5, Young Eun Choi5, Hye Jin Song 2,5, Hee Jang Pyeon2,5, Sung Soo Kim1,5, Yoon Kyung Bae1,5, Jeong Seob Won1,5, Ji Yoon Hwang2,5, So Yeong Cho2,5, Hyun Nam3,5, Hye Won Lee1,4*, Kyeung Min Joo1,2,3,5* 1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology (SAIHST), Sungkyunkwan University; 2Department of Anatomy and Cell biology, Sungkyunkwan University School of Medicine; 3Stem Cell and Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center; 4Department of Urology, Samsung Medical Center; 5Single Cell Network Research Center, Sungkyunkwan University School of Medicine *Corresponding Author
Single cell transcriptome analysis provides information on the characteristics of individual cells in a heterogeneous tumor tissue. The transcriptome analysis could be connected to specific genotype for therapeutic target validation. In this study, we tried to find personalized therapeutic targets using single cell transcriptome data for a chemo-resistance metastatic muscle invasive bladder cancer (MIBC) patient. 1,527 single cells were isolated from the MIBC tissue. At single cell transcriptome analysis, tumor cells showed gene expression matched with basal type bladder cancer. Non-cancer cells were more than 75% of isolated cells and consisted of T lymphocytes, monocytes, fibroblast, muscle cells and endothelial cells. In whole genome sequencing, HRAS Q61R mutation was detected which is known as an activation mutation. Although variant allele frequency (VAF) of HRAS Q61R was as low as 20%, transcriptome data indicated activation of RAS oncogenes including constitutive activation of downstream kinase cascades. Moreover, HRAS alone was highly expressed in tumor cells in single cell transcriptome analysis whereas overexpression of HRAS was not seen in bulk genetic analysis. Since the HRAS Q61R was specifically dysregulated in tumor cells, the HRAS pathway might be underlying mechanism of chemotherapy resistance in this tumor. Based on its functional potentials, Tipifarnib, a specific farnesyltransferase inhibitor, that blocks membrane localization of RAS was tested against patient-derived xenografts and showed significant therapeutic effects. Fortunately, the effects were also reproduced in patient. Although the tumor showed resistance to conventional chemotherapy, the patient had partial response (reduced tumor masses in both metastatic and primary tumors) after tipifarnib treatment. Additional single cell transcriptome analysis could be applied to this patient as follow-up strategies for possible therapeutic resistance to tipifarnib. Especially, immune check point inhibitors might be candidates since tumor cells and monocytes displayed high expression of PD-L1 and T lymphocytes expressed high PD-1 in single cell transcriptome analysis. Altogether the results of this study demonstrated the clinical implications of single cell transcriptome analysis that can identify rare tumor cells in tumor mass and personalized therapeutic target against the tumor cells.
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