Three-dimensional (3D) cell culture models of human epithelial organogenesis are powerful platforms for understanding mechanisms of normal organogenesis and for modeling organ-specific disease in a culture setting.
We generate breast epithelial acini-like structures using MCF-10A, an immortalized human mammary epithelia cell line. This has been a robust experimental platform to understand how epithelial cells grow into proliferation-arrested 3D epithelial structures with a hollow central lumen; how cell polarity is established and maintained during epithelial morphogenesis; how extracellular matrix is assembled during morphogenesis and understand mechanisms of tumor-initiation and progression.
More recently we developed a new method to induce formation of pancreatic ductal and acinar epithelial structures from human pluripotent stem cells. These exocrine cells generate three-dimensional dutal and acinar structures with cell-type specific biological traits both in culture and when transplanted in to mice. These models are being used in our laboratory for understanding the role played by cell polarity pathways during exocrine organogenesis and for modeling pancreatic diseases such as pancreatitis and tumor-initiation.
MCF-10A 3D morphogenes: Images acquired from Day 2 to Day 10.
Muthuswamy, S.K., Li, D., Lelivere, S., Bissell, M. and Brugge, J.S., ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat. Cell Biol 3: 785-792, 2001. PMID: 11533657
Debnath, J., Muthuswamy, S.K., Brugge, J.S., Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30:256-268, 2003. PMID: 12798140
Xiang, B. and Muthuswamy, S.K., Using three-dimensional acinar structures for molecular and cell biological assays. Methods Enzymol, 406: p. 692-701, 2006. PMID: 16472698
Wang, H, Lacoche, S, Huang, L, Xue, B, Muthuswamy, SK. Rotational motion during three-dimensional morphogenesis of mammary epithelial acini relates to laminin matrix assemble, Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):163-8. PMID: 23248267
Huang, L., Holtzinger A., Jagan, I., BeGora, , Lohse, I., Ngai, N., Nostro, C., Wang, R., Muthuswamy, L.B., Crawford, H.C., Cheryl Arrowsmith, C., Kalloger, S.E., Renouf, D.J., Connor, A., Cleary, S., Schaeffer, D.F., Roehrl, M., Tsao, M., Gallinger, S., Keller, G., and Muthuswamy, S.K. (2015) Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell– and patient-derived tumor organoids. Nat Med. 2015 Nov;21(11):1364-71. PMID: 26501191