| Module Leaders |
Dr Jane Visvader |
|
Dr Geoffrey Lindeman
|
| Host Organisation |
Walter and Eliza Hall Institute |
Module description
Research on adult epithelial stem cells has been limited by the lack of quantitative and reproducible model systems. The overall goal of this project is to define and characterise stem and progenitor cells within normal human breast tissue and to establish this as a generic model for the study of other epithelial organs and malignancies. Epithelial cancers (including breast, colorectal, lung and prostate cancer) account for 80% of human malignancies.
In order to isolate human mammary stem cells (MaSCs), the laboratory have recently employed an analogous approach to that previously described for the mouse mammary stem cell. Three distinct human epithelial subpopulations were defined and one subset exhibited mammary regenerating capacity upon implantation into ‘humanised’ mouse fat pads. This work (unpublished) represents an outcome of ASCC funding. The proposal herein directly builds on the module’s previous work, with the primary aims of establishing a robust model for epithelial stem cell transplantation and further delineating the nature of the epithelial hierarchy at both the molecular and cellular levels.
Aims
- To enhance the efficiency of xenotransplantation of human mammary stem cells.
- To further fractionate mammary basal and luminal epithelial cell populations using in vivo transplantation and in vitro cellular assays.
Module Leader biography
Dr Jane Visvader co-heads the Molecular Biology group in the Victorian Breast Cancer Research Consortium, located at The Walter and Eliza Hall Institute. She has been awarded a NHMRC Senior Research Fellowship and serves on the Medical and Scientific Advisory Committee of the Cancer Council Victoria and the Scientific Advisory Council of the National Breast Cancer Foundation. Her research focuses on understanding the epithelial hierarchy in the breast tissue, as well as genes important for controlling normal mammary development and those perturbed in breast cancer.
This work has revealed the importance of several regulators to both normal development and cancer. A particularly influential contribution that our group has made to the breast cancer field has been the prospective identification and isolation of the mammary stem cell, recently published in Nature. This work has laid the foundation for understanding which cell types in breast tissue are predisposed to becoming cancer cells. Current efforts are directed towards dissecting cells in the human epithelial hierarchy and tumour-initiating cells, as well as identifying novel therapeutic markers.
Contact details
Dr Jane Visvader
Dr Geoffrey Lindeman
Selected publications
- Lindeman GJ, Wittlin S, Lada H, Naylor MJ, Santamaria M, Zhang JG, Starr R, Hilton DJ, Alexander WS, Ormandy CJ, Visvader JE. (2001). SOCS1 deficiency results in accelerated mammary gland development and rescues lactation in prolactin receptor deficient mice. Genes Dev., 15, 1631-1636. (IF 14.8; Citations 65)
- Sum EYM, Peng B, Yu X, Chen J, Byrne J, Lindeman GJ, and Visvader. JE. (2002) The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1-mediated transactivation. J. Biol. Chem., 277(10), 7849-7856. (IF 5.6; Citations 73)
- Sun T, Patoine C, Abu-Khalil A, Visvader E, Sum E, Cherry TJ, Orkin SH, Geschwind DH, Walsh CA. (2005) Early asymmetry of gene transcription between embryonic human left and right cerebral cortex. Science. 308(5729), 1794-8. (IF 26.4; Citations 50)
- Sum EYM, Segara D, Duscio B, Bath ML, Field AS, Sutherland RL, Lindeman GJ and Visvader JE. (2005) Overexpression of LMO4 induces mammary hyperplasia, promotes breast epithelial cell invasion and is a predictor of poor outcome in breast cancer. Proc. Natl Acad. Sci USA. 122(21), 7659-7664. (IF 9.6;Citations 170)
- Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat M-L,Wu L, Lindeman GJ*, Visvader JE*. (2006) Generation of a functional mammary gland from a single stem cell. Nature. 439, 84-88. *Equal senior author (IF 28.8)
- Asselin-Labat M-L, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J, Lindeman GJ, Visvader JE. (2007) Gata-3 is an essential regulator of mammary gland morphogenesis and luminal cell differentiation. Nature Cell Biol. 9(2), 201-209. (IF = 17.6)
- Vaillant F, Asselin-Labat M-L, Shackleton M, Forrest NC, Lindeman GJ, Visvader JE. (2008) The mammary progenitor marker CD61/3-integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Research. 68(19), 7711-7. (IF = 7.7)
- Bouras T, Pal B, Vaillant F, Harburg G, Asselin-Labat M-L, Oakes SR, Lindeman GJ, Visvader JE. (2008) Notch signaling regulates mammary stem cell function and luminal cell fate commitment. Cell Stem Cell. 3(4), 429-41.
- Visvader JE and Lindeman GJ. (2008) Cancer Stem Cells in solid tumours: accumulating evidence and unresolved questions. Nature Reviews Cancer. 8(10), 755-68. (IF 29.2)
- Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat M-L, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, kConFab, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE*, Lindeman GJ*. (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature Medicine (Article) In Press (Accepted June 11) *Equal Senior Author. IF 27.