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Ince LAB

Epigenetic Regulation of Cancer Stem Cells

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Investigator / Contact Person Tan Ince

Research

I. Breast Cancer Classification Ince lab developed a hypothesis-based breast cancer classification system modeled after the taxonomy of species in evolutionary biology [1-3]. This approach uses normal lineages to classify breast tumors into four hormonal states (HR) that are associated with the outcome more strongly than standard prognostic signatures [1-3].

II. Culture of Human cells Most of the standard nutrient media that form the basis of today’s culture systems are composed of 40-50 ingredients, which are not adequate to support the biochemistry of life. Ince lab developed a series of serum-free new cell culture media composed of 85 baseline ingredients[4], in which they can culture human cells without any serum, tissue extracts, feeder layers or drugs[4]. They adapted this baseline medium for normal ovarian and fallopian tube epithelia [5], T-cell acute lymphoblastic leukemia [6] and ovarian carcinoma[7] with tissue-specific modifications.

III. Epigenomic Regulation of Cancer Stem Cells (CSCs) While pan-HDAC activity has been implicated in stem cell regulation, the role of specific HDACs in the regulation of CSCs had not been explored. They showed that among the 11 HDACs, only HDAC1 & 7 are specifically over-expressed in breast CSCs, knock-down of HDAC 1&7 inhibits and overexpression augments the CSC phenotype[8]. Also, Dr. Ince’s team discovered that new HDAC isoform-specific inhibitors that simultaneously inhibit HDAC1&7 can preferentially target CSCs [8]. We also published that combined ERα, AR, and VDR expression is a more powerful predictor of BrCa outcome [3] and currently working on epigenetic regulation of CSCs by these receptors [9].

IV. Regulation of Cancer Stem Cells by Heat Shock Factor 1 Heat shock factor 1 (HSF1) has long been recognized as the master transcription factor that regulates heat shock proteins (HSPs). They discovered that HSF1 over-expression is associated with poor outcome in lung, breast and colon cancers [10, 11], but this was not related to the heat shock response [10]. Next, they demonstrated that inducible HSF1 over-expression augments and HSF1 knockdown inhibits CSC phenotype [12]. Ince lab study indicates that HSP-independent HSF1 driven mechanisms that contribute to poor outcome involves regulation of the CSC. V. Bioengineering micro-fabricated devices for medical applications: Dr. Ince’s Lab has closely collaborated with our colleagues in the Engineering department and assisted them with the development of electrical impedance spectroscopy micro-sensors capable of detecting and differentiating tumor vs. normal cells at single cell accuracy. The critical feature of this technology is that no cell labeling, device functionalization or cell capture is required. It uses magnetic forces to immobilize cells that can be coupled with many cell analysis techniques to form lab-on-a-chip devices due to the simple fabrication setup and the principle of operation [13, 14]. References: 1. Houseman EA, Ince TA. Cancer Inform.13: 53-64,(2014). 2. Santagata S, Ince TA. Expert Rev Anticancer Ther.14: 1385-1389,(2014). 3. Santagata S, Thakkar A, et al. J Clin Invest.124: 859-870,(2014). 4. Ince TA, Richardson AL, et al. Cancer Cell.12: 160-170,(2007). 5. Merritt MA, Bentink S, et al. PLoS One.8: e80314,(2013). 6. Yost AJ, Shevchuk OO, et al. Leukemia.27: 1437-1440,(2013). 7. Ince TA, Sousa AD, et al. Nat Commun.6: 7419,(2015). 8. Witt AE, Lee CW, et al. Oncogene. (2016). 9. Thakkar A, Wang B, et al. Breast Cancer Res Treat.157: 77-90,(2016). 10. Mendillo ML, Santagata S, et al. Cell.150: 549-562,(2012). 11. Santagata S, Hu R, et al. Proc Natl Acad Sci U S A.108: 18378-18383,(2011). 12. Wang B, Lee CW, et al. Breast Cancer Res Treat.153: 57-66,(2015). 13. Gajasinghe RWRL, Toprak A, et al. IEEE Sensors Journal.16: 7572-7580,(2016). 14. Gajasinghe R, Jones M, et al. IEEE Sensors Journal.18: 3486-3493,(2018).