Photo of Michael R. Freeman,  PhD

Michael R. Freeman, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 355-6054
Fax: (617) 730-0238


michael.freeman@childrens.harvard.edu

Michael R. Freeman, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Professor, Surgery, Harvard Medical School
  • David E. Retik Director of Basic Urologic Research, Urology Research, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

My research centers on understanding mechanisms of genitourinary pathology at the molecular and cellular level. Our current work centers on the role of EGF-like growth factors as soluble and membrane-anchored signaling molecules, on the intracellular signaling systems these factors regulate, and on the physiologic consequences of EGF-like growth factor pathway activation in cell regulation and disease. We have recently determined that one of the high-affinity activating ligands for the EGF receptor/ErbB1 tyrosine kinase, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is a mechanically responsive gene in bladder smooth muscle cells. This finding, and other recently published data from our laboratory, implicate this growth factor in mechanisms of bladder wound healing and hypertrophic bladder growth. We have also recently identified HB-EGF and amphiregulin, an EGF-like growth factor with a similar domain structure to HB-EGF and a similar affinity for heparin, as products of the interstitial smooth muscle cells of the human prostate. We found the HB-EGF and amphiregulin genes to be coordinately expressed in benign and malignant human prostate tissue. These factors likely serve as directional signaling molecules between the fibromuscular stroma and the epithelial compartments of the prostate. The consequences of this directional signaling system in terms of signal transduction pathway activation, mitogenesis and cell survival regulation are under investigation.

Publications

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  • Minciacchi VR, You S, Spinelli C, Morley S, Zandian M, Aspuria PJ, Cavallini L, Ciardiello C, Reis Sobreiro M, Morello M, Kharmate G, Jang SC, Kim DK, Hosseini-Beheshti E, Tomlinson Guns E, Gleave M, Gho YS, Mathivanan S, Yang W, Freeman MR, Di Vizio D. Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles. 2015; 6:11327-41. PubMed
  • Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol 2015. PubMed
  • Wen H, Lee T, You S, Park SH, Song H, Eilber KS, Anger JT, Freeman MR, Park S, Kim J. Urinary metabolite profiling combined with computational analysis predicts interstitial cystitis-associated candidate biomarkers. J Proteome Res 2015; 14:541-8. PubMed
  • Choi DY, You S, Jung JH, Lee JC, Rho JK, Lee KY, Freeman MR, Kim KP, Kim J. Extracellular vesicles shed from gefitinib-resistant nonsmall cell lung cancer regulate the tumor microenvironment. Proteomics 2014; 14:1845-56. PubMed
  • Kim J, Morley S, Le M, Bedoret D, Umetsu DT, Di Vizio D, Freeman MR. Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells: potential effects on the tumor microenvironment. Cancer Biol Ther 2014; 15:409-18. PubMed
  • Morley S, Hager MH, Pollan SG, Knudsen B, Di Vizio D, Freeman MR. Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer. Asian J. Androl. 2014. PubMed
  • Yang W, Ramachandran A, You S, Jeong H, Morley S, Mulone MD, Logvinenko T, Kim J, Hwang D, Freeman MR, Adam RM. Integration of proteomic and transcriptomic profiles identifies a novel PDGF-MYC network in human smooth muscle cells. Cell Commun. Signal 2015; 12:44. PubMed
  • Morello M, Minciacchi VR, de Candia P, Yang J, Posadas E, Kim H, Griffiths D, Bhowmick N, Chung LW, Gandellini P, Freeman MR, Demichelis F, Di Vizio D. Large oncosomes mediate intercellular transfer of functional microRNA. Cell Cycle 2013; 12:3526-36. PubMed
  • Ayala G, Morello M, Frolov A, You S, Li R, Rosati F, Bartolucci G, Danza G, Adam RM, Thompson TC, Lisanti MP, Freeman MR, Di Vizio D. Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression. J Pathol 2013; 231:77-87. PubMed
  • Park JO, Choi DY, Choi DS, Kim HJ, Kang JW, Jung JH, Lee JH, Kim J, Freeman MR, Lee KY, Gho YS, Kim KP. Identification and characterization of proteins isolated from microvesicles derived from human lung cancer pleural effusions. Proteomics 2013. PubMed
  • Solomon KR, Allott EH, Freeman MR, Freedland SJ. Words of wisdom. Re: Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1. Eur Urol 2013; 63:1128-9. PubMed
  • Freeman MR, Solomon KR. Statin Drugs and Prostate Cancer: Time to Consider Proactive Strategies in Patients. J Urol 2013. PubMed
  • Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol 2012. PubMed
  • Di Vizio D, Morello M, Dudley AC, Schow PW, Adam RM, Morley S, Mulholland D, Rotinen M, Hager MH, Insabato L, Moses MA, Demichelis F, Lisanti MP, Wu H, Klagsbrun M, Bhowmick NA, Rubin MA, D'Souza-Schorey C, Freeman MR. Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol 2012; 181:1573-84. PubMed
  • Hager MH, Morley S, Bielenberg DR, Gao S, Morello M, Holcomb IN, Liu W, Mouneimne G, Demichelis F, Kim J, Solomon KR, Adam RM, Isaacs WB, Higgs HN, Vessella RL, Di Vizio D, Freeman MR. DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Mol Med 2012; 4:743-60. PubMed
  • Kim J, Di Vizio D, Kim TK, Kim J, Kim M, Pelton K, Clinton SK, Hai T, Hwang D, Solomon KR, Freeman MR. The response of the prostate to circulating cholesterol: activating transcription factor 3 (ATF3) as a prominent node in a cholesterol-sensing network. PLoS ONE 2012; 7:e39448. PubMed
  • Kim J, Keay SK, You S, Loda M, Freeman MR. A synthetic form of frizzled 8-associated antiproliferative factor enhances p53 stability through USP2a and MDM2. PLoS ONE 2012; 7:e50392. PubMed
  • Yang W, Chung YG, Kim Y, Kim TK, Keay SK, Zhang CO, Ji M, Hwang D, Kim KP, Steen H, Freeman MR, Kim J. Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor. Mol Cell Proteomics 2011. PubMed
  • Wu X, Gao H, Ke W, Hager M, Xiao S, Freeman MR, Zhu Z. VentX trans-activates p53 and p16ink4a to regulate cellular senescence. J Biol Chem 2011. PubMed
  • Kim J, Ji M, DiDonato JA, Rackley RR, Kuang M, Sadhukhan PC, Mauney JR, Keay SK, Freeman MR, Liou LS, Adam RM. An hTERT-immortalized human urothelial cell line that responds to anti-proliferative factor. In Vitro Cell Dev Biol Anim 2011; 47:2-9. PubMed
  • Pelton K, Di Vizio D, Insabato L, Schaffner CP, Freeman MR, Solomon KR. Ezetimibe reduces enlarged prostate in an animal model of benign prostatic hyperplasia. J Urol 2010; 184:1555-9. PubMed
  • Peleg S, Sellin JH, Wang Y, Freeman MR, Umar S. SUPPRESSION OF ABERRANT TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 6 EXPRESSION IN HYPERPROLIFERATIVE COLONIC CRYPTS BY DIETARY CALCIUM. Am J Physiol Gastrointest Liver Physiol 2010; 299:G593-601. PubMed
  • Yang W, Cai Q, Lui VW, Everley PA, Kim J, Bhola N, Quesnelle KM, Zetter BR, Steen H, Freeman MR, Grandis JR. Quantitative Proteomics Analysis Reveals Molecular Networks Regulated by Epidermal Growth Factor Receptor Level in Head and Neck Cancer. J Proteome Res 2010; 9:3073-82. PubMed
  • Yang W, Di Vizio D, Kirchner M, Steen H, Freeman MR. Proteome scale characterization of human S-acylated proteins in lipid raft-enriched and non-raft membranes. Mol Cell Proteomics 2010; 9:54-70. PubMed
  • Vaezzadeh AR, Steen H, Freeman MR, Lee RS. Proteomics and opportunities for clinical translation in urological disease. J Urol 2009; 182:835-43. PubMed
  • Di Vizio D, Morello M, Sotgia F, Pestell RG, Freeman MR, Lisanti MP. An absence of stromal caveolin-1 is associated with advanced prostate cancer, metastatic disease and epithelial Akt activation. Cell Cycle 2009; 8:2420-4. PubMed
  • Kim J,Yanagihara Y,Kikugawa T,Ji M,Tanji N,Masayoshi Y,Freeman MR. A Signaling Network in Phenylephrine-induced Benign Prostatic Hyperplasia. Endocrinology 2009; 150:3576-83. PubMed
  • Di Vizio D, Kim J, Hager MH, Morello M, Yang W, Lafargue CJ, True LD, Rubin MA, Adam RM, Beroukhim R, Demichelis F, Freeman MR. Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res 2009; 69:5601-9. PubMed
  • Mukhopadhyay NK,Kim J,Cinar B,Ramachandran A,Hager MH,Di Vizio D,Adam RM,Rubin MA,Raychaudhuri P,De Benedetti A,Freeman MR. Heterogeneous nuclear ribonucleoprotein K is a novel regulator of androgen receptor translation. Cancer Res 2009; 69:2210-8. PubMed
  • Solomon KR,Pelton K,Boucher K,Joo J,Tully C,Zurakowski D,Schaffner CP,Kim J,Freeman MR. Ezetimibe is an inhibitor of tumor angiogenesis. Am J Pathol 2009; 174:1017-26. PubMed
  • Kim J,Keay SK,Freeman MR. Heparin-binding epidermal growth factor-like growth factor functionally antagonizes interstitial cystitis antiproliferative factor via mitogen-activated protein kinase pathway activation. BJU Int 2008; 103:541-6. PubMed
  • Lee RS,Monigatti F,Briscoe AC,Waldon Z,Freeman MR,Steen H. Optimizing sample handling for urinary proteomics. J Proteome Res 2008; 7:4022-30. PubMed
  • Di Vizio D,Solomon KR,Freeman MR. Cholesterol and cholesterol-rich membranes in prostate cancer: an update. Tumori 2008; 94:633-9. PubMed
  • Di Vizio D,Adam RM,Kim J,Kim R,Sotgia F,Williams T,Demichelis F,Solomon KR,Loda M,Rubin MA,Lisanti MP,Freeman MR. Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase. Cell Cycle 2008; 7:2257-67. PubMed
  • Saban MR,Backer JM,Backer MV,Maier J,Fowler B,Davis CA,Simpson C,Wu XR,Birder L,Freeman MR,Soker S,Hurst RE,Saban R. VEGF receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation. Am J Physiol Renal Physiol 2008; 295:F60-72. PubMed
  • Solomon KR, Freeman MR. Do the cholesterol-lowering properties of statins affect cancer risk? Trends Endocrinol Metab 2008; 19:113-21. PubMed
  • Centeno CJ, Freeman M. Letters to the editor. Clin Rehabil 2008; 22:377-8. PubMed
  • Lee RS, Monigatti F, Lutchman M, Patterson T, Budnik B, Steen JA, Freeman MR, Steen H. Temporal variations of the postnatal rat urinary proteome as a reflection of systemic maturation. Proteomics 2008; 8:1097-112. PubMed
  • Yang W, Steen H, Freeman MR. Proteomic approaches to the analysis of multiprotein signaling complexes. Proteomics 2008; 8:832-51. PubMed
  • Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N, Rubin MA, Yelick PC, Freeman MR. The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J 2007; 26:4523-34. PubMed
  • Dimitrakov J, Kroenke K, Steers WD, Berde C, Zurakowski D, Freeman MR, Jackson JL. Pharmacologic Management of Painful Bladder Syndrome/Interstitial Cystitis Arch Intern Med 2007; 167:1922-9. PubMed
  • Cinar B, Mukhopadhyay NK, Meng G, Freeman MR. Phosphoinositide 3-kinase-independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains. J Biol Chem 2007; 282:29584-93. PubMed
  • Kim J, Jahng WJ, Di Vizio D, Lee JS, Jhaveri R, Rubin MA, Shisheva A, Freeman MR. The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer Res 2007; 67:9229-37. PubMed
  • Mukhopadhyay NK, Cinar B, Mukhopadhyay L, Lutchman M, Ferdinand AS, Kim J, Chung LW, Adam RM, Ray SK, Leiter AB, Richie JP, Liu BC, Freeman MR. The zinc finger protein ras-responsive element binding protein-1 is a coregulator of the androgen receptor: implications for the role of the Ras pathway in enhancing androgenic signaling in prostate cancer. Mol Endocrinol 2007; 21:2056-70. PubMed
  • Kim J, Keay SK, Dimitrakov JD, Freeman MR. p53 mediates interstitial cystitis antiproliferative factor (APF)-induced growth inhibition of human urothelial cells. FEBS Lett 2007; 581:3795-9. PubMed
  • Di Vizio D, Sotgia F, Williams TM, Hassan GS, Capozza F, Frank PG, Pestell RG, Loda M, Freeman MR, Lisanti MP. Caveolin-1 is required for the upregulation of fatty acid synthase (FASN), a tumor promoter, during prostate cancer progression. Cancer Biol Ther 2007; 6:1263-8. PubMed
  • Freeman MR. Beta2 microglobulin: a surprising therapeutic target for prostate cancer and renal cell carcinoma. J Urol 2007; 178:10-1. PubMed
  • Adam RM, Mukhopadhyay NK, Kim J, Di Vizio D, Cinar B, Boucher K, Solomon KR, Freeman MR. Cholesterol sensitivity of endogenous and myristoylated Akt. Cancer Res 2007; 67:6238-46. PubMed
  • Freeman MR, Cinar B, Kim J, Mukhopadhyay NK, Di Vizio D, Adam RM, Solomon KR. Transit of hormonal and EGF receptor-dependent signals through cholesterol-rich membranes. Steroids 2006; 72:210-7. PubMed
  • Fang PK, Solomon KR, Zhuang L, Qi M, McKee M, Freeman MR, Yelick PC. Caveolin-1alpha and -1beta perform nonredundant roles in early vertebrate development. Am J Pathol 2006; 169:2209-22. PubMed
  • Estrada CR, Adam RM, Eaton SH, B. Inhibition of EGFR signaling abrogates smooth muscle proliferation resulting from sustained distension of the urinary bladder. Lab Invest 2006; 86:1293-302. PubMed
  • Mukhopadhyay NK, Ferdinand AS, Mukhopadhyay L, Cinar B, Lutchman M, Richie JP, Freeman MR, Liu BC. Unraveling androgen receptor interactomes by an array-based method: discovery of proto-oncoprotein c-Rel as a negative regulator of androgen receptor. Exp Cell Res 2006; 312:3782-95. PubMed
  • Duque JL, Loughlin KR, Adam RM, Kantoff P, Mazzucchi E, Freeman MR. Measurement of plasma levels of vascular endothelial growth factor in prostate cancer patients: relationship with clinical stage, Gleason score, prostate volume, and serum prostate-specific antigen. Clinics 2006; 61:401-8. PubMed
  • Hager MH, Solomon KR, Freeman MR. The role of cholesterol in prostate cancer. Curr Opin Clin Nutr Metab Care 2006; 9:379-85. PubMed
  • Dimitrakov JD, Kaplan SA, Kroenke K, Jackson JL, Freeman MR. Management of chronic prostatitis/chronic pelvic pain syndrome: an evidence-based approach. Urology 2006; 67:881-8. PubMed
  • Zhuang L, Kim J, Adam RM, Solomon KR, Freeman MR. Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J Clin Invest 2005; 115:959-68. PubMed
  • Kim J, Adam RM, Solomon KR, Freeman MR. Involvement of cholesterol-rich lipid rafts in interleukin-6-induced neuroendocrine differentiation of LNCaP prostate cancer cells. Endocrinology 2003; 145:613-9. PubMed
  • Freeman MR, Solomon KR. Cholesterol and prostate cancer. J Cell Biochem 2003; 91:54-69. PubMed
  • Adam RM, Danciu T, McLellan DL, Borer JG, Lin J, Zurakowski D, Weinstein MH, Rajjayabun PH, Mellon JK, Freeman MR. A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Res 2003; 63:484-90. PubMed
  • Zhuang L, Lin J, Lu ML, Solomon KR, Freeman MR. Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res 2002; 62:2227-31. PubMed
  • Freeman MR. Growing evidence that radionuclide imaging identifies management strategies that improve outcome. J Nucl Cardiol 2009; 16:844-5. PubMed
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