Dario Marchetti, Ph.D.
Professor, Departments of Pathology and Molecular & Cellular Biology
Doctor of Biology, The University of Pavia, Italy
The biology and mechanisms of brain metastasis in melanoma and breast cancers; Heparanase (HPSE) and heparan sulfate proteoglycans (HSPG) as biological modulators of tumor angiogenesis and metastasis; roles of neurotrophins/neurotrophin receptors in invasive tumors of the nervous system, perineural invasion and HPSE/HSPG roles in interactions between tumor and nervous system cells in prostate cancer.
Focus of my laboratory is to investigate mechanisms and determinants underlying brain metastasis formation, and microenvironmental interactions between normal and nervous system-invading cells.
Possessing long-term interests and 25 year working experience in the field of neurotrophic factors, my laboratories have studied roles and relevance of a family of neurotrophic factors, the neurotrophins (NT), and their receptors (NTR), and a NT-regulated extracellular matrix degradative enzyme, called heparanase (HPSE), uniquely involved in cancer invasion and metastasis, notably to brain.
Brain metastases, which occur in 30-40% of all cancer patients, are an important cause of cancer morbidity and mortality, and their frequency is rapidly increasing. Mechanisms responsible for malignant melanoma or breast cancer progression to highly aggressive brain-metastatic disease remain largely unknown. Main objective of our laboratory is to understand molecular determinants in these two cancer types, and to use this knowledge for developing novel therapies to prevent brain metastasis. We have demonstrated that the neurotrophin receptor p75NTR and neurotrophin - regulated HPSE are critical determinants of brain metastasis. HPSE represents the only mammalian endoglycosidase cleaving heparan sulfate (HS),the main polysaccharide constituent of the extracellular matrix and basement membranes as HS proteoglycans (HSPG). HPSE activity plays decisive roles in fundamental biological events associated with extracellular matrix remodeling, such as cancer metastasis, inflammation, modulation of HS-binding angiogenic growth factors and cytokines (which bound/are stored at high levels in ECM/BM HSPG) action and associated mechanisms and biological outcome.
HPSE relevance in cancer invasion and metastasis is established: HPSE over-expression/upregulation significantly correlates with the metastatic phenotype, tumor vascularity (angiogenesis), and reduced post-operative survival of patients from several cancer types. The anti-cancerous effects of hpse silencing, HPSE inhibiting molecules, and the unexpected identification of a single functional heparanase, place this enzyme as a promising target for anticancer drug development. However, precise mechanisms of its action, e.g., nuclear presence/functionality, splice variants expression, gene regulation, post-transcriptional regulation, etc., are not fully understood nor is the “HPSE system” including, besides HPSE, heparanase-2 (a HPSE-related protein not possessing enzymatic activity or known function) and its isoforms, the HPSE processing enzyme and a cell - surface HPSE receptor.
We have demonstrated HPSE functionality in other brain tumors, notably human medullobastoma, the most common and devastating brain tumor of childhood. Our working hypotheses for the involvement of neurotrophin receptors (NTR) and HPSE in medulloblastoma are:
1) p75NTRmediates MB cell invasion and tumorigenicity while other NTR (i.e., the TrkC NT receptor) do not;
2) HPSE is regulated by p75NTR – mediated mechanisms in MB; and3) HPSE plays pivotal roles in human MB cell invasion and tumorigenicity.
My laboratory aims to test these hypotheses and determine a) the mechanisms of HPSE regulation and MB cell invasion bysiRNA – mediated specific MB cell knockdowns; and b) the effects on MB cells tumorigenicity by a modulation of p75NTR and HPSE expression. These studies are consistent with the following model:
1) p75NTR possesses unique biological functions in MB; and
2) HPSE is expressed, NT-regulated, and functionally relevant in MB invasive and tumorigenic events.
We have extensive collaborations with clinicians and researchers at M.D. Anderson Cancer Center-Houston, Texas Children Hospital-Houston, the Genome Center at Baylor College of Medicine, and the Stehlin Foundation for Cancer Research. Sixty-seven peer-reviewed scientific articles and reviews of past research are available on-line
S'Souza D., Yang W., Marchetti, D. , Muir C., Julian J., Farach-Carson M., and Carson D.D. HIP/RLP29 antagonizes VEGF and FGF2 responses. Journ. of Cell. Biochem., 106(2): 200-209, 2009.
Brown, A.J., Alicknavitch, M., D'Souza, S.S., Daikoku, T., Kirn-Safran, C., Marchetti, D., Carson, D.D., and Farach-Carson, M.C. Heparanase expression and activity influences chondrogenic and osteogenic processes during endochondral bone formation. Bone, 43(4): 689-699, 2008.
Murry, B.P., Blust, B., Singh, A., Foster, T., and Marchetti, D. Heparanase mechanisms of melanoma metastasis to the brain: development and use of a brain slice model. Journ. Cell. Biochem., 97(2): 217-225, 2006.
Sinnappah-Kang, N., Mrak, R.E., Paulsen, D.D., and Marchetti, D. Prognostic implications of heparanase and TrkC/p75 NTR expression in human medulloblastoma. Clin. & Exp. Metastasis, 23: 55 -63, 2006.
Moretti, M.*, Sinnappah-Kang, N*, Toller, M., Curcio, F, and Marchetti, D. Heparanase functionality in olfactory neural cells. Journ. Neurosci. Res., 83: 694-701, 2006. *These Authors contributed equally well.
Reiland, J., Kempf, D., Roy , M., Denkins, Y., and Marchetti, D. FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells. Neoplasia, 8(7): 596-606, 2006.
Roy, M., Reiland, J., Chouljenko, V., Kousoulas, K.G., and Marchetti, D. Antisense mediated suppression of heparanase gene inhibits melanoma cell invasion. Neoplasia, 7(3): 253-262, 2005.
Murry, B.P., Greiter-Wilke, A., Paulsen, D.B., Hiatt, K.M., Beltrami, C.A., and Marchetti, D. Selective heparanase localization in malignant melanoma cancers. Int. Journ. Oncology, 26: 345-352, 2005.
Reiland, J., Sanderson, R. D., Waguespack, M., Barker, S., Long, R., Carson, D. D. , and Marchetti, D. Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. Journ. of Biol. Chemistry, 279(9): 8047-8055, 2004.
Aucoin, R., Reiland, J., Roy , M., and Marchetti, D. Dominant-negative CREB inhibits heparanase functionality and melanoma cell invasion. Journ. Cell. Biochem., 93(2): 215-223, 2004.
Marchetti, D., Reiland, J., Erwin, B., and Roy , M. Inhibition of heparanase activity and heparanase-induced angiogenesis by suramin analogues. Int. Journ. Cancer, 104(2): 167-174, 2003.
Marchetti, D., and Nicolson, G.L. Human heparanase: a molecular determinant of invasion and angiogenesis. Adv. Enzyme Reg., 41: 343-360, 2001.
Marchetti, D., Li, J., and Shen, R-J. Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Research, 60: 4767-4770, 2000.
Walch, E.T., Albino, A.P., and Marchetti, D. Over-expression of the low-affinity p75 neurotrophin receptor correlates with augmented invasion and heparanase production in human malignant melanoma cells. Int. Journ. Cancer, 82: 112-120, 1999.
Walch, E.T., and Marchetti, D. Role of neurotrophins and neurotrophin receptors in the in vitro invasion and heparanase production of human prostatic cancer cells. Clin. & Exp. Metastasis, 17(4): 307-314, 1999.
For more publications, see listing on PubMed.
Department of Pathology