Email:  marchett@bcm.edu

Specialty: Biology and Diagnostics of CTC ; Brain-metastatic melanoma; Heparanase; Heparan sulfate processing; Brain-metastatic breast cancer; Mechanisms of medulloblastoma invasion and tumorigenicity.

Research Interests: 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 CNS cells. The biology and prognostic utility of Circulating Tumor Cells (CTC) in metastatic cancers and Circulating Endothelial Cells (CEC) in Type2 Diabetes.

Prospectus: 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 a multi-decade 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 functional mammalian endoglycosidase cleaving heparan sulfate (HS), the main polysaccharide constituent of the extracellular matrix and basement membranes as HS proteoglycans (HSPG). HPSE 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.