Program Official

Principal Investigator

Awardee Organization

University Of New Mexico Health Scis Ctr
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Mechanisms of melanoma brain metastasis by CTCs isolated from patients' blood and CSF

Melanoma Brain Metastasis (MBM) carries a dismal prognosis with a median overall survival of only 4-6 months. If patients develop leptomeningeal disease, the overall survival is even lower. The incidence of MBM has been reported to be up to 43% in clinical settings and up to 75% in the autopsy series. Although notions that Circulating Tumor Cells (CTCs) act as “seeds” of intractable metastasis are established, there is no knowledge characterizing MBM-colonizing CTCs. Single-cell CTC transcriptional profiling has also demonstrated that CTCs isolated from patients are very distinct from cell lines that are widely used for drug discovery. This is even more compelling considering that significant discrepancies of biomarkers among CTCs and corresponding primary and metastatic tumors have been observed. Moreover, while the presence of CTCs in the cerebrospinal fluid (CSF) remains the gold standard, the sensitivity of cytology is only 50-56% at time of the first CSF analysis. Therefore, the development of effective therapy approaches - CTC-based tests - could have a tremendous clinical impact to treat MBM. We hypothesize that the neurotrophin receptor p75NTR and Heparanase (HPSE), two markers implicated in MBM models, are novel CTC biomarkers to predict clinical MBM and potential therapeutic targets to prevent MBM. The objective of this application is to demonstrate that the p75NTR/HPSE axis is diagnostic in clinical MBM; and that p75NTR and HPSE are novel therapeutic CTC targets to combat MBM. In aim 1, we will: a) isolate and characterize p75NTR/HPSE CTC subsets from blood and CSF (multiparametric flow cytometry and DEPArrayTM technologies among others), and compare the expression of p75NTR/HPSE combinations in CTCs of melanoma patients diagnosed either with or without MBM; b) directly link patient-isolated CTC subsets, possessing p75NTR/HPSE expression and combinations, to clinical MBM. In aim 2, we will assess effects of regulating functions of p75NTR/HPSE CTC subsets on MBM development by using small-molecule p75NTR and new HPSE inhibitors along with CTC xenografts; and complement these effects with regulatory p75NTR/HPSE gene expression (pINDUCER lentiviral toolkit). In aim 3, we will: a) determine roles of CTC-expressed Merlin as an important integrator of p75NTR/HPSE pathways altering CTC proliferation vs. growth arrest; b) delineate HPSE-induced, syndecan-mediated modulation of Merlin/Hippo signaling to affect CTC properties driving MBM. Uncovering MBM CTC phenotypes offers the opportunity to modify treatment by extending studies directly to human melanoma. This project lead by an inter-disciplinary and well-integrated team will study and validate new and specific CTC biomarkers responsible for CTC-induced MBM. It has high therapeutic impact and is paradigmshifting. We are uniquely positioned to perform this study not only for having access to an extensive cohort of blood/CSF samples from melanoma patients but also for the extensive expertise interrogating the entire CTC spectrum by combining multiple and complementary CTC technologies unlike other groups in the country.


  • Ridgway LD, Wetzel MD, Marchetti D. Modulation of GEF-H1 induced signaling by heparanase in brain metastatic melanoma cells. Journal of cellular biochemistry. 2010 Dec 1;111(5):1299-309. PMID: 20803552
  • Guerrero PA, Yin W, Camacho L, Marchetti D. Oncogenic role of Merlin/NF2 in glioblastoma. Oncogene. 2015 May 14;34(20):2621-30. Epub 2014 Jul 21. PMID: 25043298
  • 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. Journal of cellular biochemistry. 2008 Dec 1;105(5):1183-93. PMID: 18980226
  • Bowley TY, Merkley SD, Lagutina IV, Ortiz MC, Lee M, Tawfik B, Marchetti D. Targeting Translation and the Cell Cycle Inversely Affects CTC Metabolism but Not Metastasis. Cancers. 2023 Nov 2;15. (21). PMID: 37958436
  • Ridgway LD, Wetzel MD, Marchetti D. Heparanase Modulates Shh and Wnt3a Signaling in Human Medulloblastoma Cells. Experimental and therapeutic medicine. 2011 Mar 1;2(2):229-238. PMID: 21442027
  • 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. Science translational medicine. 2013 Apr 10;5(180):180ra48. PMID: 23576814
  • Vishnoi M, Liu NH, Yin W, Boral D, Scamardo A, Hong D, Marchetti D. The identification of a TNBC liver metastasis gene signature by sequential CTC-xenograft modeling. Molecular oncology. 2019 Sep;13(9):1913-1926. Epub 2019 Jun 19. PMID: 31216110
  • Ridgway LD, Wetzel MD, Ngo JA, Erdreich-Epstein A, Marchetti D. Heparanase-induced GEF-H1 signaling regulates the cytoskeletal dynamics of brain metastatic breast cancer cells. Molecular cancer research : MCR. 2012 Jun;10(6):689-702. Epub 2012 Apr 18. PMID: 22513363
  • Zhang L, Sullivan P, Suyama J, Marchetti D. Epidermal growth factor-induced heparanase nucleolar localization augments DNA topoisomerase I activity in brain metastatic breast cancer. Molecular cancer research : MCR. 2010 Feb;8(2):278-90. PMID: 20164500
  • Zhang L, Sullivan PS, Goodman JC, Gunaratne PH, Marchetti D. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. Cancer research. 2011 Feb 1;71(3):645-54. Epub 2011 Jan 25. PMID: 21266359
  • Bowley TY, Marchetti D. Application of CTC discoveries for liquid biopsy: the RPL/RPS gene signature of melanoma CTCs is linked to brain metastasis onset. Clinical & experimental metastasis. 2024 Jan 12. Epub 2024 Jan 12. PMID: 38212568
  • Roy M, Marchetti D. Cell surface heparan sulfate released by heparanase promotes melanoma cell migration and angiogenesis. Journal of cellular biochemistry. 2009 Feb 1;106(2):200-9. PMID: 19115257
  • Bowley TY, Lagutina IV, Francis C, Sivakumar S, Selwyn RG, Taylor E, Guo Y, Fahy BN, Tawfik B, Marchetti D. The RPL/RPS gene signature of melanoma CTCs associates with brain metastasis. Cancer research communications. 2022 Nov;2(11):1436-1448. Epub 2022 Nov 16. PMID: 36407834
  • Boral D, Liu HN, Kenney SR, Marchetti D. Molecular Interplay between Dormant Bone Marrow-Resident Cells (BMRCs) and CTCs in Breast Cancer. Cancers. 2020 Jun 19;12. (6). PMID: 32575420
  • Vishnoi M, Boral D, Liu H, Sprouse ML, Yin W, Goswami-Sewell D, Tetzlaff MT, Davies MA, Oliva ICG, Marchetti D. Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow-Resident Melanoma CTCs. Cancer research. 2018 Sep 15;78(18):5349-5362. Epub 2018 Jul 19. PMID: 30026332