Anna L. Means, Ph.D.
Assistant Professor of Surgery and Cell & Developmental Biology
Vanderbilt University Medical Center
Nashville, TN 37232-2733
Pancreatic cancer; tumor microenvironment; growth factor signaling; pancreas development; oncogenes
Work in my lab investigates signaling pathways that regulate cell-cell interactions during development of pancreatic cancer. In particular, we are interested in how the epidermal growth factor receptor (EGFR) and one of its ligands, heparin-binding epidermal growth factor-like growth factor (HB-EGF), coordinately regulate both epithelial tumorigenesis and the fibrosis that forms the microenvironment surrounding the developing tumor. We have found that the initiation of pancreatic cancer does not follow the classic paradigm seen in colon cancer where loss of a tumor suppressor gene initiates tumorigenesis and then acquisition of an oncogene promotes tumor formation. The pancreas seems to require two oncogenic events to initiate and promote tumorigenesis with tumor suppressors acting later to increase progression to malignant disease. In the mouse models we have designed, the two oncogenes that are sufficient to initiate and promote pancreatic cancer are KrasG12D and elevated expression of HB-EGF. We are currently understanding how these two oncogenes synergize at the molecular level. We are also investigating targeting the normal source of HB-EGF, inflammatory cells, to determine whether HB-EGF alone or in concert with other cytokines produced by inflammatory cells is necessary for tumor formation.
In a related line of investigation, we have found that overexpression of HB-EGF also increases fibrosis in the pancreas. Fibrosis is a consistent character in pancreatic cancer and likely provides the signals necessary for survival and growth of the tumor and well as providing a barrier to chemotherapeutic treatment. We are using mouse models in conjunction with human tissue analysis to understand how this fibrosis arises and how it can be altered to allow access of chemotherapeutic agents to the tumor.
We have found that epithelium and mesenchyme/stroma are also coordinately regulated during embryonic development. Understanding how interactions between these tissues are regulated will indicate pathways that may also function in those interactions that occur during tumorigenesis in the adult. During embryonic development, mesenchyme (embryonic stroma) is critical for pancreatic development even though only the epithelium gives rise to the pancreas. Removal of surrounding mesenchyme prevents growth and alters the differentiation profile of the pancreatic epithelium. We have found that blocking EGFR signaling has a similar effect to removing the surrounding mesenchyme -- growth is severely compromised and differentiation is altered. We have localized EGFR protein at the epithelial-mesenchymal interface, supporting our hypothesis that EGFR signaling mediates the crosstalk between these two tissues.
All of this work uses a variety of experimental approaches. We use transgenes and gene knockouts to study regulatory processes in vivo. Whenever possible, we correlate our findings back to human pancreatic cancer tissues. We also do culture of cells and tissues isolated from mice to manipulate signaling events in controlled, measurable ways. We use physiology, histology, and molecular biology to understand development and disease on a holistic basis, all the way from the individual to the organ to the tissue and finally to the molecules within cells.
- Ray, KC, Bell, KM, Yan, J, Gu, G, Chung, CH, Washington, MK, Means, AL Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. PLoS One, 6(2), e16786, 2011.
- Blaine, SA, Ray, KC, Anunobi, R, Gannon, MA, Washington, MK, Means, AL Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling. Development, 137(14), 2289-96, 2010.
- Blaine, SA, Ray, KC, Branch, KM, Robinson, PS, Whitehead, RH, Means, AL Epidermal growth factor receptor regulates pancreatic fibrosis. Am J Physiol Gastrointest Liver Physiol, 297(3), G434-41, 2009.
- Zhang, H, Ables, ET, Pope, CF, Washington, MK, Hipkens, S, Means, AL, Path, G, Seufert, J, Costa, RH, Leiter, AB, Magnuson, MA, Gannon, M Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation. Mech Dev, 126(11-12), 958-73, 2009.
- Ray, KC, Blaine, SA, Washington, MK, Braun, AH, Singh, AB, Harris, RC, Harding, PA, Coffey, RJ, Means, AL Transmembrane and soluble isoforms of heparin-binding epidermal growth factor-like growth factor regulate distinct processes in the pancreas. Gastroenterology, 137(5), 1785-94, 2009.
- Means, AL, Xu, Y, Zhao, A, Ray, KC, Gu, G A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis, 46(6), 318-23, 2008.
- Nomura, S, Settle, SH, Leys, CM, Means, AL, Peek, RM, Leach, SD, Wright, CV, Coffey, RJ, Goldenring, JR Evidence for repatterning of the gastric fundic epithelium associated with MÃ©nÃ©trier's disease and TGFalpha overexpression. Gastroenterology, 128(5), 1292-305, 2005.
- Means, AL, Chytil, A, Moses, HL, Coffey, RJ, Wright, CV, Taketo, MM, Grady, WM Keratin 19 gene drives Cre recombinase expression throughout the early postimplantation mouse embryo. Genesis, 42(1), 23-7, 2005.
- Means, AL, Meszoely, IM, Suzuki, K, Miyamoto, Y, Rustgi, AK, Coffey, RJ, Wright, CV, Stoffers, DA, Leach, SD Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development, 132(16), 3767-76, 2005.
- Matsuoka, Taka-aki, Artner, Isabella, Henderson, Eva, Means, Anna, Sander, Maike, Stein, Roland The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc Natl Acad Sci U S A, 101(9), 2930-3, 2004.
- Matsuoka, Taka-aki, Zhao, Li, Artner, Isabella, Jarrett, Harry W, Friedman, David, Means, Anna, Stein, Roland Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol, 23(17), 6049-62, 2003.
- Means, Anna L, Ray, Kevin C, Singh, Amar B, Washington, M Kay, Whitehead, Robert H, Harris, Raymond C, Wright, Christopher V E, Coffey, Robert J, Leach, Steven D Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology, 124(4), 1020-36, 2003.
- Samaras, Susan E, Zhao, Li, Means, Anna, Henderson, Eva, Matsuoka, Taka-Aki, Stein, Roland The islet beta cell-enriched RIPE3b1/Maf transcription factor regulates pdx-1 expression. J Biol Chem, 278(14), 12263-70, 2003.
- Meszoely, I M, Means, A L, Scoggins, C R, Leach, S D Developmental aspects of early pancreatic cancer. Cancer J, 7(4), 242-50, 2001.
- Means, A L, Leach, S D Lineage commitment and cellular differentiation in exocrine pancreas. Pancreatology, 1(6), 587-96, 2001.
- Means, A L, Thompson, J R, Gudas, L J Transcriptional regulation of the cellular retinoic acid binding protein I gene in F9 teratocarcinoma cells. Cell Growth Differ, 11(2), 71-82, 2000.
- Scoggins, C R, Meszoely, I M, Wada, M, Means, A L, Yang, L, Leach, S D p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am J Physiol Gastrointest Liver Physiol, 279(4), G827-36, 2000.
- Means, A L, Gudas, L J The CRABP I gene contains two separable, redundant regulatory regions active in neural tissues in transgenic mouse embryos. Dev Dyn, 209(1), 59-69, 1997.
- Means, A L, Gudas, L J FGF-2, BMP-2, and BMP-4 regulate retinoid binding proteins and receptors in 3T3 cells. Cell Growth Differ, 7(8), 989-96, 1996.
- Means, A L, Gudas, L J The roles of retinoids in vertebrate development. Annu Rev Biochem, 64201-33, 1995.
- Means, A L, Slansky, J E, McMahon, S L, Knuth, M W, Farnham, P J The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter. Mol Cell Biol, 12(3), 1054-63, 1992.
- Farnham, P J, Means, A L Sequences downstream of the transcription initiation site modulate the activity of the murine dihydrofolate reductase promoter. Mol Cell Biol, 10(4), 1390-8, 1990.
- Means, A L, Farnham, P J Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site. Mol Cell Biol, 10(2), 653-61, 1990.