Faculty Appointments
Research Professor of Plastic Surgery
Research Professor of Cell & Developmental Biology
Education
Ph.D., University of Wisconsin, Milwaukee, WisconsinB.S., Ohio University, Athens, Ohio
Office Address
D2300 Medical Center North
Dept. of Surgery
1161 21st Ave. S.
Nashville, TN 37232-2733
Dept. of Surgery
1161 21st Ave. S.
Nashville, TN 37232-2733
Research Description
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.
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.
Research Keywords
Pancreatic cancer; tumor microenvironment; growth factor signaling; pancreas development; oncogenes
Publications
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. 2011; 6(2): e16786. PMID: 21311774, PMCID: PMC3032792, DOI: 10.1371/journal.pone.0016786, ISSN: 1932-6203.
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 [print-electronic]. 2010 Jul; 137(14): 2289-96. PMID: 20534672, PMCID: PMC2889602, PII: dev.048421, DOI: 10.1242/dev.048421, ISSN: 1477-9129.
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 [print-electronic]. 2009 Dec; 126(11-12): 958-73. PMID: 19766716, PMCID: PMC2783291, PII: S0925-4773(09)01453-1, DOI: 10.1016/j.mod.2009.09.006, ISSN: 1872-6356.
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 [print-electronic]. 2009 Nov; 137(5): 1785-94. PMID: 19689925, PMCID: PMC2767440, PII: S0016-5085(09)01399-7, DOI: 10.1053/j.gastro.2009.07.067, ISSN: 1528-0012.
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 [print-electronic]. 2009 Sep; 297(3): G434-41. PMID: 19608732, PMCID: PMC2739824, PII: 00152.2009, DOI: 10.1152/ajpgi.00152.2009, ISSN: 1522-1547.
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. 2008 Jun; 46(6): 318-23. PMID: 18543299, PMCID: PMC3735352, DOI: 10.1002/dvg.20397, ISSN: 1526-968X.
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 [print-electronic]. 2005 Aug; 132(16): 3767-76. PMID: 16020518, PII: dev.01925, DOI: 10.1242/dev.01925, ISSN: 0950-1991.
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 Ménétrier's disease and TGFalpha overexpression. Gastroenterology. 2005 May; 128(5): 1292-305. PMID: 15887112, PII: S0016508505004038, ISSN: 0016-5085.
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. 2005 May; 42(1): 23-7. PMID: 15828001, DOI: 10.1002/gene.20119, ISSN: 1526-954X.
Matsuoka TA, Artner I, Henderson E, Means A, Sander M, Stein R. The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2004 Mar 3/2/2004; 101(9): 2930-3. PMID: 14973194, PMCID: PMC365722, PII: 0306233101, DOI: 10.1073/pnas.0306233101, ISSN: 0027-8424.
Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R. Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol. Cell. Biol. 2003 Sep; 23(17): 6049-62. PMID: 12917329, PMCID: PMC180917, ISSN: 0270-7306.
Samaras SE, Zhao L, Means A, Henderson E, Matsuoka TA, Stein R. The islet beta cell-enriched RIPE3b1/Maf transcription factor regulates pdx-1 expression. J. Biol. Chem [print-electronic]. 2003 Apr 4/4/2003; 278(14): 12263-70. PMID: 12551916, PII: M210801200, DOI: 10.1074/jbc.M210801200, ISSN: 0021-9258.
Means AL, Ray KC, Singh AB, Washington MK, Whitehead RH, Harris RC, Wright CV, Coffey RJ, Leach SD. Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology. 2003 Apr; 124(4): 1020-36. PMID: 12671899, PII: S0016508503000647, DOI: 10.1053/gast.2003.50150, ISSN: 0016-5085.
Meszoely IM, Means AL, Scoggins CR, Leach SD. Developmental aspects of early pancreatic cancer. Cancer J. 2001 Jul; 7(4): 242-50. PMID: 11561600, ISSN: 1528-9117.
Means AL, Leach SD. Lineage commitment and cellular differentiation in exocrine pancreas. Pancreatology. 2001; 1(6): 587-96. PMID: 12120241, PII: S1424-3903(01)80006-5, DOI: 10.1159/000055868, ISSN: 1424-3903.
Scoggins CR, Meszoely IM, Wada M, Means AL, Yang L, Leach SD. P53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 2000 Oct; 279(4): G827-36. PMID: 11005771, ISSN: 0193-1857.
Means AL, Thompson JR, Gudas LJ. Transcriptional regulation of the cellular retinoic acid binding protein I gene in F9 teratocarcinoma cells. Cell Growth Differ. 2000 Feb; 11(2): 71-82. PMID: 10714763, ISSN: 1044-9523.
Means AL, Gudas LJ. The CRABP I gene contains two separable, redundant regulatory regions active in neural tissues in transgenic mouse embryos. Dev. Dyn. 1997 May; 209(1): 59-69. PMID: 9142496, PII: 10.1002/(SICI)1097-0177(199705)209:1<59::AID-AJA6>3.0.CO;2-W, DOI: 10.1002/(SICI)1097-0177(199705)209:1<59::AID-AJA6>3.0.CO;2-W, ISSN: 1058-8388.
Means AL, Gudas LJ. FGF-2, BMP-2, and BMP-4 regulate retinoid binding proteins and receptors in 3T3 cells. Cell Growth Differ. 1996 Aug; 7(8): 989-96. PMID: 8853894, ISSN: 1044-9523.
Means AL, Gudas LJ. The roles of retinoids in vertebrate development. Annu. Rev. Biochem. 1995; 64: 201-33. PMID: 7574480, DOI: 10.1146/annurev.bi.64.070195.001221, ISSN: 0066-4154.
Means AL, Slansky JE, McMahon SL, Knuth MW, Farnham PJ. The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter. Mol. Cell. Biol. 1992 Mar; 12(3): 1054-63. PMID: 1545788, PMCID: PMC369537, ISSN: 0270-7306.
Farnham PJ, Means AL. Sequences downstream of the transcription initiation site modulate the activity of the murine dihydrofolate reductase promoter. Mol. Cell. Biol. 1990 Apr; 10(4): 1390-8. PMID: 2320003, PMCID: PMC362241, ISSN: 0270-7306.
Means AL, Farnham PJ. Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site. Mol. Cell. Biol. 1990 Feb; 10(2): 653-61. PMID: 2300058, PMCID: PMC360863, ISSN: 0270-7306.
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 [print-electronic]. 2010 Jul; 137(14): 2289-96. PMID: 20534672, PMCID: PMC2889602, PII: dev.048421, DOI: 10.1242/dev.048421, ISSN: 1477-9129.
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 [print-electronic]. 2009 Dec; 126(11-12): 958-73. PMID: 19766716, PMCID: PMC2783291, PII: S0925-4773(09)01453-1, DOI: 10.1016/j.mod.2009.09.006, ISSN: 1872-6356.
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 [print-electronic]. 2009 Nov; 137(5): 1785-94. PMID: 19689925, PMCID: PMC2767440, PII: S0016-5085(09)01399-7, DOI: 10.1053/j.gastro.2009.07.067, ISSN: 1528-0012.
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 [print-electronic]. 2009 Sep; 297(3): G434-41. PMID: 19608732, PMCID: PMC2739824, PII: 00152.2009, DOI: 10.1152/ajpgi.00152.2009, ISSN: 1522-1547.
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. 2008 Jun; 46(6): 318-23. PMID: 18543299, PMCID: PMC3735352, DOI: 10.1002/dvg.20397, ISSN: 1526-968X.
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 [print-electronic]. 2005 Aug; 132(16): 3767-76. PMID: 16020518, PII: dev.01925, DOI: 10.1242/dev.01925, ISSN: 0950-1991.
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 Ménétrier's disease and TGFalpha overexpression. Gastroenterology. 2005 May; 128(5): 1292-305. PMID: 15887112, PII: S0016508505004038, ISSN: 0016-5085.
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. 2005 May; 42(1): 23-7. PMID: 15828001, DOI: 10.1002/gene.20119, ISSN: 1526-954X.
Matsuoka TA, Artner I, Henderson E, Means A, Sander M, Stein R. The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2004 Mar 3/2/2004; 101(9): 2930-3. PMID: 14973194, PMCID: PMC365722, PII: 0306233101, DOI: 10.1073/pnas.0306233101, ISSN: 0027-8424.
Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R. Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol. Cell. Biol. 2003 Sep; 23(17): 6049-62. PMID: 12917329, PMCID: PMC180917, ISSN: 0270-7306.
Samaras SE, Zhao L, Means A, Henderson E, Matsuoka TA, Stein R. The islet beta cell-enriched RIPE3b1/Maf transcription factor regulates pdx-1 expression. J. Biol. Chem [print-electronic]. 2003 Apr 4/4/2003; 278(14): 12263-70. PMID: 12551916, PII: M210801200, DOI: 10.1074/jbc.M210801200, ISSN: 0021-9258.
Means AL, Ray KC, Singh AB, Washington MK, Whitehead RH, Harris RC, Wright CV, Coffey RJ, Leach SD. Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia. Gastroenterology. 2003 Apr; 124(4): 1020-36. PMID: 12671899, PII: S0016508503000647, DOI: 10.1053/gast.2003.50150, ISSN: 0016-5085.
Meszoely IM, Means AL, Scoggins CR, Leach SD. Developmental aspects of early pancreatic cancer. Cancer J. 2001 Jul; 7(4): 242-50. PMID: 11561600, ISSN: 1528-9117.
Means AL, Leach SD. Lineage commitment and cellular differentiation in exocrine pancreas. Pancreatology. 2001; 1(6): 587-96. PMID: 12120241, PII: S1424-3903(01)80006-5, DOI: 10.1159/000055868, ISSN: 1424-3903.
Scoggins CR, Meszoely IM, Wada M, Means AL, Yang L, Leach SD. P53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 2000 Oct; 279(4): G827-36. PMID: 11005771, ISSN: 0193-1857.
Means AL, Thompson JR, Gudas LJ. Transcriptional regulation of the cellular retinoic acid binding protein I gene in F9 teratocarcinoma cells. Cell Growth Differ. 2000 Feb; 11(2): 71-82. PMID: 10714763, ISSN: 1044-9523.
Means AL, Gudas LJ. The CRABP I gene contains two separable, redundant regulatory regions active in neural tissues in transgenic mouse embryos. Dev. Dyn. 1997 May; 209(1): 59-69. PMID: 9142496, PII: 10.1002/(SICI)1097-0177(199705)209:1<59::AID-AJA6>3.0.CO;2-W, DOI: 10.1002/(SICI)1097-0177(199705)209:1<59::AID-AJA6>3.0.CO;2-W, ISSN: 1058-8388.
Means AL, Gudas LJ. FGF-2, BMP-2, and BMP-4 regulate retinoid binding proteins and receptors in 3T3 cells. Cell Growth Differ. 1996 Aug; 7(8): 989-96. PMID: 8853894, ISSN: 1044-9523.
Means AL, Gudas LJ. The roles of retinoids in vertebrate development. Annu. Rev. Biochem. 1995; 64: 201-33. PMID: 7574480, DOI: 10.1146/annurev.bi.64.070195.001221, ISSN: 0066-4154.
Means AL, Slansky JE, McMahon SL, Knuth MW, Farnham PJ. The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter. Mol. Cell. Biol. 1992 Mar; 12(3): 1054-63. PMID: 1545788, PMCID: PMC369537, ISSN: 0270-7306.
Farnham PJ, Means AL. Sequences downstream of the transcription initiation site modulate the activity of the murine dihydrofolate reductase promoter. Mol. Cell. Biol. 1990 Apr; 10(4): 1390-8. PMID: 2320003, PMCID: PMC362241, ISSN: 0270-7306.
Means AL, Farnham PJ. Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site. Mol. Cell. Biol. 1990 Feb; 10(2): 653-61. PMID: 2300058, PMCID: PMC360863, ISSN: 0270-7306.