Thomas Jefferson University Office of Faculty Affairs

Main menu:

Faculty Affairs: Faculty Interests Database Michael Phillip Lisanti, M.D., Ph.D.

Jefferson
Professor of Cancer Biology
Professor of Medical Oncology
Professor of Biochemistry and Molecular Biology
Leader, Program in Molecular Biology and Genetics of Cancer
Kimmel Cancer Center
Thomas Jefferson University
Appointed: 2006
Mailing Address Contact Information
233 S. 10th Street, BLSB
Philadelphia, Pennsylvania 19107
United States
Phone: 215-503-9295
Fax: 215-923-1098
michael.lisanti@kimmelcancercenter.org
Personal Web Site
Qualifications
B.A., New York University, Chemistry, 1985
Ph.D., Cornell University Medical College, Cell Biology and Genetics, 1991
M.D., Cornell University Medical College, Medicine, 1992
Visiting Scientist, Rockefeller University, NY, 1991-1992
Fellow, Whitehead Institute/Massachusetts Institute of Technology (MIT), Cambridge, MA, 1992-1997
Expertise and Research Interests
Caveolin-1 in Signaling, Cancer, and Stem Cell Biology

The focus of my laboratory is to understand, at the molecular and cellular level, the role of caveolin-1 (Cav-1) in i) normal signaling and ii) pathogenic signaling during the development of human cancers. Our work over the last decade directly demonstrates that Cav-1 functions as a brake during signal transduction, akin to the behavior of other tumor suppressor genes.

At the molecular level, Cav-1 contains a 20-amino acid region that we have termed the caveolin-scaffolding domain (CSD). This region functions as a modular protein domain that recognizes a well-defined caveolin-binding motif (CBM) present in many classes of signaling molecules, especially protein kinases. Thus, we have proposed that Cav-1, via its scaffolding domain, functions as a broad-spectrum kinase inhibitor. This explains Cav-1''s ability to act as a natural endogenous inhibitor of the p42/44-MAP kinase cascade, as well as other mitogenic signaling pathways, and initiate cell cycle arrest in the Go/G1 phase of the cell cycle. We are currently assessing the activity of a variety of caveolin-mimetic peptides that can be used as potential therapeutics.

At the cellular level, we have recently focused on the mammary epithelial cell. We have shown that sporadic Cav-1 mutations occur at high frequency in human breast cancers (about one-third of estrogen-receptor positive patients harbor a dominant-negative Cav-1 mutation). Thus, we have used Cav-1 (-/-) mice (generated in my laboratory) as a model system to study the effect of loss-of-caveolin-function on the behavior of the mammary gland, both in vivo and ex vivo. Our results show that loss of Cav-1 in vivo results in mammary epithelial cell hyperplasia, a pre-malignant mammary lesion, and increased susceptibility towards mammary tumorigenesis. Ex vivo, our studies with primary cultures of Cav-1 (-/-) mammary epithelia show many interesting phenotypes, such as increased proliferation, defects in 3D-lumen formation, growth-factor independence, as well as increased cell invasiveness and epithelial branching. At the molecular level, these phenotypes are due to the constitutive activation of key signaling pathways normally repressed by Cav-1, involving ERK-1/2, Smad-2/3, and Stat5a hyper-activation, as well as increased expression of estrogen receptor (ER-alpha), Cyclin D1, and MMP-2/9. Thus, loss-of-Cav-1 function provides a novel initiating mechanism for human cancers, as Cav-1 normally suppresses a plethora of pro-proliferative signaling pathways. We have also observed the Cav-1 (-/-) mice show hyper-proliferation in other epithelial compartments, such as the basal keratinocyte layer of the skin and in the crypts of the small intestine.

Given that Cav-1 is highly expressed in terminally differentiated cells, its absence may lead to an increase in adult epithelial stem cell populations. This could explain some of the tumor suppressor effects of Cav-1, as it functions to maintain cells in a differentiated non-proliferative state. In direct support of this hypothesis, we have recently shown that Cav-1 (-/-) mice have increased levels of both mammary stem cells and intestinal crypt stem cells. These studies provide direct support for the idea that cancer stem cells should be targeted for caveolin-replacement therapy.

Other Expertise
I have worked in many different areas of patho-physiology. Currently, my lab focuses on the following major topics, and we have numerous publications in each category during the last 10 years.

Cardiomyopathy and Lung Disease (Pulmonary Hypertension and Fibrosis)
Atherosclerosis, Diabetes, and Obesity
Stroke and Neurodegenerative Diseases
Immunity, Inflammation, and Infectious Disease
Muscular Dystrophy
Aging
Cancer, Signaling, Cell Cycle Progression, and Stem Cell Biology

My laboratory is currently ranked in the Top 100 most-cited labs world-wide. See the following:

Top 100 Most-Cited Researchers in Biochemistry & Biology (THOMSON ISI) Based on Impact Factors- during a 10.5 year period (1/1/96-6/30/06)

Ranked # 13 World-wide

See www.in-cites.com/nobel/2006-bio-top100.html
Industrial Relevance
Our work has the potential for the development for therapeutics for a variety of human diseases, including breast and prostate cancer, diabetes, heart failure, atherosclerosis, stroke, muscular dystrophy, and bladder dysfunction.
Keywords
caveolae; caveolin; signaling; cancer; stem cells; pathology; physiology; animal models of human disease
Languages
English; working knowledge of Spanish and Italian.
Publications
  • Honors and Awards. 1981, Top 40 Winner, Westinghouse Science Talent Search, National Navy Science Award; 1984, American Chemical Society Analytical Chemistry Award, Lucy G. Moses Scholarship; 1985, University Honors Scholar, George Granger Brown Prize for Chemistry and Physics, Merk & Co. Book Award for Chemistry, graduated Magna cum laude, Phi Beta Kappa; 1988, Dean''s Research Prize; 1990, Julian R. Rachele Prize, Dean''s Research Prize and Vincent du Vingneaud Prize; 1991, Dean''s Research Thesis Award; 1993, NIH FIRST Award; 1995, Elsa U. Pardee Foundation Grant; 1997, Charles E. Culpeper Foundation--New Faculty Award, Mathers Charitable Foundation Grant; 1998, Sidney Kimmel Cancer Research Foundation Award, Melini Award; 1999, Albert Einstein Research Achievement Award--External selection committee consisted of Drs. Levine, Sabatini, and Silverstein; given to the most outstanding faculty members at Einstein; 2001, The Bensley Award, American Association of Anatomists
  • Dr. Lisanti has over 270 publications. Only a select number of publications are listed here.
  • Ju X, Katiyar S, Wang C, Liu M, Li S, Jiao X, Zhou J, Turner J, Lisanti MP, Russell RG, Mueller S, Ojeifo J, Chen WS, Hay N, Pestell RG. 2007. Akt1 governs breast cancer progression in vivo. Proc. Natl. Acad. Sci, USA, 104: 7438-43.
  • Li T, Sotgia F, Vuolo MA, Li M, Yang WC, Pestell RG, Sparano JA, Lisanti MP. 2006. Caveolin-1 Mutations in Human Breast Cancer: Functional Association with Estrogen Receptor (ER-_lpha) Positive Status. Am J Pathol. 168: 1998-2013.
  • Sotgia F, Williams TM, Schubert W, Medina F, Minetti C, Pestell RG, Lisanti MP. 2006. Caveolin-1 deficiency (-/-) conveys premalignant alterations in mammary epithelia, with abnormal lumen formation, growth factor independence, and cell invasiveness. Am J Pathol. 168: 292-309.
  • Sotgia F, Schubert W, Pestell RG, Lisanti MP. 2006. Genetic Ablation of Caveolin-1 in Mammary Epithelial Cells Increases Milk Production and Hyper-Activates STAT5a Signaling. Cancer Biol Ther. 5: 292-297.
  • Sotgia F, Williams TM, Cohen AW, Minetti C, Pestell RG, Lisanti MP. 2005. Caveolin-1-deficient mice have an increased mammary stem cell population with upregulation of Wnt/beta-catenin signaling. Cell Cycle. 4:1808-16.
  • Iyengar P, Espina V, Williams TW, Lin Y, Berry D, Jelicks LA, Lee H, Temple K, Graves R, Pollard J, Chopra N, Russell RG, Sasisekharan R, Trock BJ, Lippman M, Calvert VS, Petricoin EF, Liotta L, Dadachova E, Pestell RG, Lisanti MP, Bonaldo P, Scherer PE. 2005. Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J Clin Invest. 115: 1163-1176.
  • Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y, Lisanti MP, Albanese C, Katzenellenbogen BS, Kushner PJ, Weber B, Rosen EM, Pestell RG. 2005. Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity. Cancer Res. 65: 6557-67.
  • Williams TM, Medina F, Badano I, Hazan RB, Hutchinson J, Muller WJ, Chopra NG, Scherer PE, Pestell RG, Lisanti MP. 2004. Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo: Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion. J Biol Chem. 279: 51630-46.
  • Williams TM, Lee H, Cheung MW, Cohen AW, Razani B, Iyengar P, Scherer PE, Pestell RG, Lisanti MP. 2004. Combined loss of INK4a and caveolin-1 synergistically enhances cell proliferation and oncogene-induced tumorigenesis: Role of INK4a/CAV-1 in mammary epithelial cell hyperplasia. J Biol Chem. 279: 24745-56.
  • Williams TM, Cheung MW, Park DS, Razani B, Cohen AW, Muller WJ, Di Vizio D, Chopra NG, Pestell RG, Lisanti MP. 2003. Loss of caveolin-1 gene expression accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice. Mol Biol Cell. 14: 1027-42.
  • Park DS, Lee H, Frank PG, Razani B, Nguyen AV, Parlow AF, Russell RG, Hulit J, Pestell RG, Lisanti MP. 2002. Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade. Mol Biol Cell. 13: 3416-30.
  • Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C, Flanagan L, Tenniswood MP, Guha C, Lisanti MP, Pestell RG, Scherer PE. 2003. Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene. 22: 6408-23.
  • Lee H, Park DS, Razani B, Russell RG, Pestell RG, Lisanti MP. 2002. Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia. Am J Pathol. 161: 1357-69.
  • Park DS, Lee H, Riedel C, Hulit J, Scherer PE, Pestell RG, Lisanti MP. 2001. Prolactin negatively regulates caveolin-1 gene expression in the mammary gland during lactation, via a Ras-dependent mechanism. J Biol Chem. 276: 48389-97.
  • Engelman JA, Zhang XL, Lisanti MP. 1999. Sequence and detailed organization of the human caveolin-1 and -2 genes located near the D7S522 locus (7q31.1). Methylation of a CpG island in the 5'' promoter region of the caveolin-1 gene in human breast cancer cell lines. FEBS Lett. 448: 221-30.
  • Engelman JA, Zhang XL, Lisanti MP. 1998. Genes encoding human caveolin-1 and -2 are co-localized to the D7S522 locus (7q31.1), a known fragile site (FRA7G) that is frequently deleted in human cancers. FEBS Lett. 436:403-10.
  • Engelman JA, Lee RJ, Karnezis A, Bearss DJ, Webster M, Siegel P, Muller WJ, Windle JJ, Pestell RG, Lisanti MP. 1998. Reciprocal regulation of neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo. Implications for human breast cancer. J Biol Chem. 273: 20448-55.
  • Relevant Review Articles
  • Sotgia F, Rui H, Bonuccelli G, Mercier I, Pestell RG, Lisanti MP. 2006. Caveolin-1, Mammary Stem Cells, and Estrogen-Dependent Breast Cancers. (Invited MiniReview), Cancer Research, 66: 10647-51.
  • Jasmin JF, Mercier I, Sotgia F, Lisanti MP. 2006. SOCS proteins and caveolin-1 as negative regulators of endocrine signaling. Trends Endocrinol Metab. 17: 150-8.
  • Williams TM, Lisanti MP. 2005. Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol. 288: C494-506.
  • Bouras T, Lisanti MP, Pestell RG. 2004. Caveolin-1 in breast cancer. Cancer Biol Ther. 3: 931-41.
  • Razani B, Lisanti MP. 2001. Caveolin-deficient mice: Insights into caveolar function and human disease. J Clin Invest. 108: 1553-61.
  • Galbiati F, Razani B, Lisanti MP. 2001. Emerging themes in lipid rafts and caveolae. Cell. 106: 403-11.

Last Updated by KT Ferrera: Monday, December 3, 2012 2:20:11 PM

Back to top