Dr. Shiaw-Yih Lin
The University of Texas MD Anderson Cancer Center
Department of Systems Biology
DNA damage response (DDR) is a coordinated response of DNA repair and activation of checkpoints. DDR protects against genomic instability, a major characteristic that promotes all cancer hallmarks. Since defects of DDR are unique and required for all cancer, they serve as ideal targets for effective cancer treatment and as robust biomarkers for early cancer detection and prevention. Our research aims to apply Systems Biology approaches to develop comprehensive DDR defects profiles (DNA, RNA, protein signatures) for cancer detection, prevention and personalized cancer therapy. Two of the major projects are described below:
(1) Develop comprehensive DDR defect signatures and corresponding targeted therapies.
By genome-wide gene expression profiling to systematically measure the cellular transcriptome reprogramming in cells with homologous recombination DNA repair defect (HRD), we have successfully developed a gene signature that represents the defect of homologous recombination (HR) DNA repair. This gene signature can faithfully predict the HRD in cells. To apply this invention in clinic, we have further optimized HRD and developed a 10-gene signature that robustly predicts the sensitivity of cancer cells to PARP inhibitors. This HRD gene signature can serve as a powerful predictive tool to guide PARP inhibitor-based therapy.
Currently, we are expanding our project to develop molecular profiles (DNA, RNA and protein) that represent the defects of all other major DNA repair mechanisms, including defects of non-homologous end-joining (NHEJ), mismatch repair, base-excision repair and nucleotide excision repair and identify drugs that target on cancer with the defects of these individual DNA repair mechanisms for precision cancer therapy.
(2) Target replication stress response defect in cancer.
The defects of DDR, particularly replication stress response (RSR), play a critical role in cellular transformation and cancer initiation. RSR is a subset of DNA damage response that safeguards the replication process. RSR defect is required for the initiation of oncogene-induced cellular transformation and, therefore, can serve as a robust biomarker for early cancer detection and cancer prevention. We have successfully established two RSRD cell models in breast cancer. Using Systems Biology approaches, we discovered a link of the molecular profile of RSRD to the profile of cancer initiating cells, supporting a critical role of RSRD in cancer initiation. We further identified unique RSRD-markers and agents that target the RSRD cells. Currently we are developing nano-imaging tool to detect these cells for early cancer detection and assessing the effects of RSRD-targeting agents for cancer prevention.
In addition to these two translational projects, my lab has active projects to study the function of nuclear PTEN in maintenance of heterochromatin and tumor suppression; to investigate the role of CHD4 mutations in endometrial cancer; and to understand the molecular determinants and clinical implication of tumor dormancy in breast cancer.