Keywords
Last Name
Institution

DARIO MARCHETTI

TitleVisiting Professor
InstitutionBaylor College of Medicine
DepartmentDepartment of Molecular & Cellular Biology
DivisionMolecular & Cellular Biology
AddressDepartment of MCB
One Baylor Plaza, Mail Stop BCM 130
Houston TX 77030
vCardDownload vCard

    Collapse Additional Tools and Researcher Information 
    Collapse Faculty Mentor
    Collapse Verify Publications

    Collapse Overview 
    Collapse overview
    The scientific focus of Dr. Marchetti’s laboratory is penetrating research to improve understandings of mechanisms underlying brain metastasis; this, by capturing changes in the brain microenvironment and investigating determinants implicated in the early events of tumor cell colonization to brain. The ultimate objective is to apply concepts and findings clinically for novel and effective treatments combating brain metastasis.

    Specifically, we aim to:

    1. Determine how heparanase, a master regulator of cancer metastasis, affects the onset of brain metastasis via enzymatic and non – enzymatic functions, and at multiple levels, e.g., tumor cell adhesion, vascular cooption, disruption of the blood-brain-barrier, cytoskeletal dynamics, tumor cell extravasation/growth, and promoting chemotherapy resistance.
    2. Identify subsets, and investigate properties and molecular signatures of Circulating Tumor Cells (CTCs) – the “seeds” of uncurable metastatic disease – as unique alternative to invasive biopsies for the detection, diagnosis, and monitoring of tumors with a predilection to metastasize to brain.

    Brain metastasis remains the most devastating and feared consequence of cancer with more than 40% of all cancer patients developing brain metastasis. For example, patients with brain metastatic breast cancer (BMBC) have, even with the best available treatments, only a 20% one-year survival rate. BMBC is particularly common in breast cancers that are positive for epidermal growth factor receptor1 and 2 (EGFR and HER2), however, targeted therapies against BMBC, e.g., lapatinib – a EGFR/HER2 dual kinase inhibitor, are only minimally effective with response rates lower than those for extracranial metastases. The identification of mechanisms responsible for BMBC is imperative to develop new therapies.

    By several pre-clinical studies, my laboratories have demonstrated that heparanase (HPSE) acts as a potent pro-tumorigenic, pro-angiogenic, and pro-metastatic enzyme. Heparanase is the only endoglycosidase in mammals which cleaves heparan sulfate (HS), the main polysaccharide of cell surface and tumor-surrounding extracellular matrix, into fragments retaining biological activity. An established role for heparanase is to release HS-bound growth and angiogenic factors stored in the extracellular matrix, and regulate their levels and potency, thus initiating many effects which drastically alter the metastatic outcome. These functions are mediated by enzymatically active heparanase. However, recent findings indicate that heparanase possesses functions which are independent of its enzymatic activity, and acts as an adhesion molecule and signal transducer. The therapeutic disruption of heparanase therefore provides an opportunity to block multiple pathways that control tumor-host interactions and are crucial for tumor growth and metastasis.

    Our work has implicated heparanase as a promoter of brain metastasis whose activity is highest in cells metastasizing to brain. The enzyme is also produced by cells of the brain microenvironment in response to a brain neoplastic insult fostering metastatic growth. Further, we have demonstrated that heparanase is expressed in BMBC tissues, and functions as a target of EGFR/HER2 pathways affecting BMBC cell proliferation. Overall, these findings set the stage for developing therapies aimed at the heparanase/HS axis. To move toward this goal, we must gain a better understanding of the mechanisms of heparanase, which are poorly understood. By studying much broader roles for heparanase, which involve enzymatic and non-enzymatic functions, and deciphering these roles at distinct steps of brain colonization, we aim to demonstrate that heparanase regulates the cross-talk between BMBC and cells of the brain microenvironment, and initiates multiple effects which are critical for the development and progression of BMBC. Our approaches are cutting-edge and include unique in vitro and in vivo models of BMBC, lentiviral delivery targeting heparanase with microRNA, small molecule HPSE inhibitors, and innovative study designs of the biology of CTCs. They emphasize the strong translational component of our programs which hold a great potential for new understandings of BMBC onset and regulation. They will provide the essential groundwork to introduce heparanase-based therapies in patients with brain metastases in general, breast cancer brain metastasis in particular. We are fully dedicated to this goal.

    Contact information:

    Dario Marchetti, Ph.D, Professor, Department of Pathology & Immunology and Molecular & Cellular Biology, Director CTC Core, BCM - Taub bldg., Suite T240A.

    Phone: (713) 798-2335. Fax: (713) 798-1956. E-mail: marchett@bcm.edu.

    Collapse keywords
    Brain Metastasis, Breast Cancer, Mechanisms of Cancer Invasion and Metastasis, Circulating Tumor Cells, Heparanase, Notch1, Merlin, Cancer Stem Cell Markers, The Brain-Metastasis Selected Marker CTC Profile, CTC subset characterization, Malignant Melanoma, Uveal Melanoma, CTC Biomarker Discovery and Validation.


    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Boral D, Vishnoi M, Liu HN, Yin W, Sprouse ML, Scamardo A, Hong DS, Tan TZ, Thiery JP, Chang JC, Marchetti D. Molecular characterization of breast cancer CTCs associated with brain metastasis. Nat Commun. 2017 Aug 04; 8(1):196. PMID: 28775303.
      View in: PubMed
    2. Vishnoi M, Peddibhotla S, Yin W, T Scamardo A, George GC, Hong DS, Marchetti D. The isolation and characterization of CTC subsets related to breast cancer dormancy. Sci Rep. 2015; 5:17533. PMID: 26631983.
      View in: PubMed
    3. Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D, Dotti G. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015 May; 21(5):524-9. PMID: 25849134.
      View in: PubMed
    4. Zhang L, Ngo JA, Wetzel MD, Marchetti D. Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer. Neoplasia. 2015 Jan; 17(1):101-13. PMID: 25622903; PMCID: PMC4309682.
    5. Guerrero PA, Yin W, Camacho L, Marchetti D. Oncogenic role of Merlin/NF2 in glioblastoma. Oncogene. 2015 May 14; 34(20):2621-30. PMID: 25043298; PMCID: PMC4302072.
    6. Camacho L, Guerrero P, Marchetti D. MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes. PLoS One. 2013; 8(9):e73790. PMID: 24066071; PMCID: PMC3774795.
    7. Zhang L, Ridgway LD, Wetzel MD, Ngo J, Yin W, Kumar D, Goodman JC, Groves MD, Marchetti D. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med. 2013 Apr 10; 5(180):180ra48. PMID: 23576814; PMCID: PMC3863909.
    8. Guo L, Fan D, Zhang F, Price JE, Lee JS, Marchetti D, Fidler IJ, Langley RR. Selection of brain metastasis-initiating breast cancer cells determined by growth on hard agar. Am J Pathol. 2011 May; 178(5):2357-66. PMID: 21514446; PMCID: PMC3081177.
    9. Ridgway LD, Wetzel MD, Marchetti D. Heparanase Modulates Shh and Wnt3a Signaling in Human Medulloblastoma Cells. Exp Ther Med. 2011 Mar 01; 2(2):229-238. PMID: 21442027.
      View in: PubMed
    10. Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. Cancer Res. 2011 Feb 1; 71(3):645-54. PMID: 21266359; PMCID: PMC3078691.
    11. Ridgway LD, Wetzel MD, Marchetti D. Modulation of GEF-H1 induced signaling by heparanase in brain metastatic melanoma cells. J Cell Biochem. 2010 Dec 1; 111(5):1299-309. PMID: 20803552; PMCID: PMC3007595.
    12. Roy M, Marchetti D. Cell surface heparan sulfate released by heparanase promotes melanoma cell migration and angiogenesis. J Cell Biochem. 2009 Feb 1; 106(2):200-9. PMID: 19115257; PMCID: PMC2736788.
    13. D'Souza S, Yang W, Marchetti D, Muir C, Farach-Carson MC, Carson DD. HIP/RPL29 antagonizes VEGF and FGF2 stimulated angiogenesis by interfering with HS-dependent responses. J Cell Biochem. 2008 Dec 1; 105(5):1183-93. PMID: 18980226; PMCID: PMC4287213.
    14. Sinnappah-Kang ND, Mrak RE, Paulsen DB, Marchetti D. Heparanase expression and TrkC/p75NTR ratios in human medulloblastoma. Clin Exp Metastasis. 2006; 23(1):55-63. PMID: 16826429.
      View in: PubMed
    15. Reiland J, Kempf D, Roy M, Denkins Y, Marchetti D. FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells. Neoplasia. 2006 Jul; 8(7):596-606. PMID: 16867222; PMCID: PMC1601937.
    16. Moretti M, Sinnappah-Kang ND, Toller M, Curcio F, Marchetti D. HPSE-1 expression and functionality in differentiating neural cells. J Neurosci Res. 2006 Mar; 83(4):694-701. PMID: 16429446.
      View in: PubMed
    17. Murry BP, Blust BE, Singh A, Foster TP, Marchetti D. Heparanase mechanisms of melanoma metastasis to the brain: Development and use of a brain slice model. J Cell Biochem. 2006 Feb 1; 97(2):217-25. PMID: 16288472.
      View in: PubMed
    18. Sinnappah-Kang ND, Kaiser AJ, Blust BE, Mrak RE, Marchetti D. Heparanase, TrkC and p75NTR: their functional involvement in human medulloblastoma cell invasion. Int J Oncol. 2005 Sep; 27(3):617-26. PMID: 16077909.
      View in: PubMed
    19. Denkins Y, Kempf D, Ferniz M, Nileshwar S, Marchetti D. Role of omega-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma. J Lipid Res. 2005 Jun; 46(6):1278-84. PMID: 15772428.
      View in: PubMed
    20. Roy M, Reiland J, Murry BP, Chouljenko V, Kousoulas KG, Marchetti D. Antisense-mediated suppression of Heparanase gene inhibits melanoma cell invasion. Neoplasia. 2005 Mar; 7(3):253-62. PMID: 15799825; PMCID: PMC1501137.
    21. Murry BP, Greiter-Wilke A, Paulsen DP, Hiatt KM, Beltrami CA, Marchetti D. Selective heparanase localization in malignant melanoma. Int J Oncol. 2005 Feb; 26(2):345-52. PMID: 15645118.
      View in: PubMed
    22. Aucoin R, Reiland J, Roy M, Marchetti D. Dominant-negative CREB inhibits heparanase functionality and melanoma cell invasion. J Cell Biochem. 2004 Oct 1; 93(2):215-23. PMID: 15368349.
      View in: PubMed
    23. Denkins Y, Reiland J, Roy M, Sinnappah-Kang ND, Galjour J, Murry BP, Blust J, Aucoin R, Marchetti D. Brain metastases in melanoma: roles of neurotrophins. Neuro Oncol. 2004 Apr; 6(2):154-65. PMID: 15134630; PMCID: PMC1871977.
    24. Marchetti D, Aucoin R, Blust J, Murry B, Greiter-Wilke A. p75 neurotrophin receptor functions as a survival receptor in brain-metastatic melanoma cells. J Cell Biochem. 2004 Jan 1; 91(1):206-15. PMID: 14689592.
      View in: PubMed
    25. Reiland J, Sanderson RD, Waguespack M, Barker SA, Long R, Carson DD, Marchetti D. Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J Biol Chem. 2004 Feb 27; 279(9):8047-55. PMID: 14630925.
      View in: PubMed
    26. Marchetti D, Denkins Y, Reiland J, Greiter-Wilke A, Galjour J, Murry B, Blust J, Roy M. Brain-metastatic melanoma: a neurotrophic perspective. Pathol Oncol Res. 2003; 9(3):147-58. PMID: 14530807.
      View in: PubMed
    27. Marchetti D, Murry B, Galjour J, Wilke-Greiter A. Human melanoma TrkC: its association with a purine-analog-sensitive kinase activity. J Cell Biochem. 2003 Apr 1; 88(5):865-72. PMID: 12616526.
      View in: PubMed
    28. Marchetti D, Reiland J, Erwin B, Roy M. Inhibition of heparanase activity and heparanase-induced angiogenesis by suramin analogues. Int J Cancer. 2003 Mar 20; 104(2):167-74. PMID: 12569571.
      View in: PubMed
    29. Marchetti D, Parikh N, Sudol M, Gallick GE. Stimulation of the protein tyrosine kinase c-Yes but not c-Src by neurotrophins in human brain-metastatic melanoma cells. Oncogene. 1998 Jun 25; 16(25):3253-60. PMID: 9681823.
      View in: PubMed
    30. Nicolson GL, Menter DG, Herrmann JL, Yun Z, Cavanaugh P, Marchetti D. Brain metastasis: role of trophic, autocrine, and paracrine factors in tumor invasion and colonization of the central nervous system. Curr Top Microbiol Immunol. 1996; 213 ( Pt 2):89-115. PMID: 9053298.
      View in: PubMed
    31. Marchetti D, McCutcheon I, Ross M, Nicolson G. Inverse expression of neurotrophins and neurotrophin receptors at the invasion front of human-melanoma brain metastases. Int J Oncol. 1995 Jul; 7(1):87-94. PMID: 21552811.
      View in: PubMed
    32. Marchetti D, Haverkamp LJ, Clark RC, McManaman JL. Ontogeny of high- and low-affinity nerve growth factor receptors in the lumbar spinal cord of the developing chick embryo. Dev Biol. 1991 Nov; 148(1):306-13. PMID: 1657663.
      View in: PubMed
    33. McManaman JL, Oppenheim RW, Prevette D, Marchetti D. Rescue of motoneurons from cell death by a purified skeletal muscle polypeptide: effects of the ChAT development factor, CDF. Neuron. 1990 Jun; 4(6):891-8. PMID: 2361012.
      View in: PubMed
    MARCHETTI's Networks
    Click the "See All" links for more information and interactive visualizations!
    Concepts Expand Description
    _
    Co-Authors Expand Description
    _
    Similar People Expand Description
    _
    Same Department Expand Description
    Physical Neighbors Expand Description
    _