APPLICATIONS OF TECHNOLOGY:
- Testing potential therapeutics to
- prevent cancer progression to immortality and malignancy
- reverse immortalization in cancer cells
- Assays to identify agents that promote immortalization and malignancy
- Generation of immortal and malignant lines from any individual’s normal HMEC
- Unique technology using pathologically relevant agents
- Immortalization occurs without gross genomic errors
- Allows determination of errors driving immortalization of human cancer cells in the absence of passenger errors
Update: 2015 Publication in Epigenics
Martha Stampfer and James Garbe of Berkeley Lab and their colleagues at the University of Arizona have developed an advanced human cell culture technology that for the first time allows experimental examination of the immortalization step in human cancer progression and provides a method to assay therapeutics that could inhibit cancer progression at the premalignant stage.
The Berkeley Lab approach is the first to efficiently and reproducibly immortalize normal human mammary epithelial cells (HMEC) using agents associated with breast cancer development in vivo. The technology is based on the Berkeley Lab researchers’ discovery that the introduction of a common breast cancer–associated oncogene into HMEC with a defective retinoblastoma pathway will induce expression of telomerase, the enzymatic activity required for immortality.
Since immortalization is necessary for human cells to become carcinomas, targeted therapeutics that prevent or reverse immortalization could be of great value in the prevention or treatment of a wide range of human cancers, including multiple breast cancer subtypes. The Berkeley Lab invention, which directly inactivates tumor-suppressive barriers to produce transformed human cell lines lacking passenger errors, will facilitate identifying and targeting the processes that drive the immortalization of cancer cells in humans.
The Berkeley Lab invention represents a significant advancement in breast cancer research. Studies that utilize small short-lived animals such as mice to study cancer progression are unable to examine the immortalization step since mouse cells, unlike human, do not normally suppress telomerase activity and can spontaneously immortalize. Previous work with human cells has been unable to achieve reproducible immortalization using agents that mimic in vivo processes during carcinogenesis. By directly targeting the tumor-suppressive senescence barriers in normal human cells, the Berkeley Lab researchers have discovered the key to overcoming the most difficult barrier in the prevention of cancer progression, and to providing a method for examining this process and developing effective therapies.
DEVELOPMENT STAGE: Proven principle
STATUS: U.S. Patent No. 10689652, issued on 23-Jun-2020. Available for licensing or collaborative research.
FOR MORE INFORMATION:
Vrba, L., Garbe, J., Stampfer, M. Futscher, B. (2015). A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers. Epigenics, 10:11, 1074-1083.
Garbe, JC, Vrba, L, Sputova, K, Fuchs, L, Novak, P, Brothman, AR, Jackson, M, Chin, K, LaBarge, MA, Watts, G, Futscher, BW, Stampfer, MR (2014). Immortalization of Normal Human Mammary Epithelial Cells in Two Steps by Direct Targeting of Senescence Barriers Does Not Require Gross Genomic Alterations. Cell Cycle, 13:3423-35.
Researcher’s website: http://hmec.lbl.gov/mindex.html
Other method references:
Garbe JC, Bhattacharya S, Merchant B, Bassett E, Swisshelm K, Feiler HS, Wyrobek AJ, Stampfer MR (2009). Molecular distinctions between the stasis and telomere attrition senescence barriers demonstrated by long-term culture of normal human mammary epithelial cells. Cancer Res 69:7557-68.
LaBarge MA, Garbe JC, Stampfer MR (2013). Processing of human reduction mammoplasty and mastectomy tissues for cell culture. J Visualized Experimentation 71: e50011.
Stampfer MR, LaBarge MA, Garbe JC (2013). An Integrated Human Mammary Epithelial Cell Culture System for Studying Carcinogenesis and Aging , in: Cell and Molecular Biology of Breast Cancer, ed. H. Schatten, Springer, NY pp323-361.
Papers using this new methodology:
Garcia, H, Miecznikowski, JC, Safina, A, Commane, M, Ruusulehto, A, Kilpinen, S, Leach, RW, Attwood, K, Li, Y, Degan, S, Omilian, AR, Guryanova, O, Papantonopoulou, O, Wang, J, Buck, M, Liu, S, Morrison, C, Gurova, KV (2013). Facilitates Chromatin Transcription Complex Is an ‘‘Accelerator’’ of Tumor Transformation and Potential Marker and Target of Aggressive Cancers Cell Rep 4, 159–73.
Pelissier, FA, Garbe, JC, Ananthanarayanan, B, Miyano, M, Lin, C, Jokela, T, Kumar, S, Stampfer, MR, Lorens, JB, LaBarge, LA (2014). Age-related dysfunction in mechano-transduction impairs differentiation of human mammary epithelial progenitors. Cell Reports 7:1926-39.
SEE THESE OTHER BERKELEY LAB TECHNOLOGIES IN THIS FIELD:
Tracking and Quantifying Organization of Epithelial Cells, IB-2903
Long Term Growth of Finite Life Span Normal Human Epithelial Cells, IB-2077
REFERENCE NUMBER: 2013-168