Faculty

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Yves Albert Declerck, MD
Professor of Pediatrics and Biochemistry and Molecular Medicine (Part Time)
Pediatrics
CHL Mail Stop 54 Off Campus Los Angeles
+1 323 361 2150

Overview

Yves DeClerck MD is a Pediatrician-Scientist at Children’s Hospital Los Angeles and USC. He is leading a cancer biology research program focused on the tumor microenvironment. He is the co-leader of the Tumor Microenvironment Program at the USC-Norris Comprehensive Cancer Center and the Director for Research Education at the Children’s Center for Cancer and Blood Disease.
Research Focus of the Laboratory: The main focus of investigation in our laboratory is on the Tumor Microenvironment (TME) and its contribution to cancer progression and metastasis (Borriello et al., Cancer Lett. 2016). The main objective of the laboratory is to understand fundamental mechanisms of communication between tumor cells and stromal cells in the TME in order to identify targets for therapeutic intervention that can be tested in relevant pre-clinical models. These data are then used to design early phase clinical trials in children with cancer through collaboration with clinical investigators at the USC-Norris Comprehensive Cancer Center and Children’s Hospital Los Angeles (CHLA). A major focus is on Neuroblastoma (NB), the second most common solid tumor in children and a cancer that is highly metastatic. Our research approach combines cell and molecular biology with pre-clinical animal models in mice. Our research program has 3 major directions:
1. Contribution of cancer-associated fibroblasts (CAF) to neuroblastoma progression: Our laboratory has recently identified in neuroblastoma tumors, CAFs that share phenotypic and functional properties of bone marrow mesenchymal stromal cells (MSC). These cells are educated by NB cells toward a pro-tumorigenic function that enhance NB cell proliferation, survival and drug-resistance through the production of several pro-tumorigenic cytokines and chemokines such as IL-6, IL-8, VEGF, SDF1 and MCP1 (Borriello et al., Cancer Res. 2017, in press). Downstream of these cytokines is the activation of STAT3 and ERK1/2 in NB cells. Ongoing work investigates the effect of blocking STAT3 and ERK1/2 in combination with chemotherapy and immunotherapy to enhance therapeutic response and prevent resistance.
2. Contribution of exosomes and extracellular vesicles to the education of CAFs, MSCs and macrophages by tumor cells: Stromal cells in the TME are educated by tumor cells and polarized toward a pro-tumorigenic function (these cells from being foes learn to become friends of the tumor cells). Extracellular vesicles and in particular exosomes released by tumor cells are captured by stromal cells and contribute to their education not only in primary tumors but also in the pre-metastatic niche. Our laboratory has recently shown (Nakata et al., Journal of Extracellular Vesicles 2017, in press) that exosomes released by NB cells are captured by MSCs and macrophages and contribute to the production of pro-tumorigenic cytokines by these cells. Ongoing work is studying the mechanism involved in the capture of tumor-derived exosomes by MSCs and macrophages with a focus on galectin-3 binding protein and integrins in collaboration with Dr. Lyden at Cornell (NYU) and on identifying ways to inhibit the production of exosomes by tumor cells and its effect on tumor progression and metastasis in pre-clinical mouse models.
3. Role of plasminogen activator inhibitor-1 (PAI-1) in cancer progression: PAI-1 is a serine protease inhibitor which has been shown to have a paradoxically positive effect in cancer progression by promoting angiogenesis and protecting tumor cells from drug-induced apoptosis (Placencio et al., Cancer Res, 2016). More recent work in our laboratory shows that PAI-1 contributes to inflammation in cancer by promoting the recruitment of macrophages into tumors and their polarization (or education) toward a pro-tumorigenic (M2) phenotype.
Funding of the Laboratory: Our laboratory has been funded by the NIH without interruption since 1986. Current funding incudes 2 R01 grants (work on exosomes described under #2, and work on PAI-1 described under #3), and a project in a larger multi-institutional program project grant on neuroblastoma (work under #1).
Environment: Our laboratory is located on the 5th floor of the Smith Research Tower at The Saban Research Institute (TSRI) of Children’s Hospital Los Angeles (CHLA). Our research program is part of the Tumor Microenvironment Program of the USC Norris Comprehensive Cancer Center (USC-Norris) and the neuroblastoma research group of the Children’s Center for Cancer and Blood Diseases at CHLA. Both TSRI and USC-Norris provide a rich and interactive environment for the conduct of innovative research in the area of the TME. We have collaborations with faculty at USC, Cornell, City of Hope, Harvard and Children’s Hospital of Philadelphia. The laboratory has trained 10 graduate students and 25 postdoctoral fellows, many presently working at academic institutions and in industry. Career development of highly motivated and dedicated students is an integral part of the research experience in the laboratory.
The Principal Investigator: Dr. DeClerck is a Tenured Professor of Pediatrics and Biochemistry & Molecular Medicine at USC. He started his career as a physician-scientist in the early 1980s and has established an independent research program that has been funded by the NIH without interruption since 1986. He has organized multiple meetings and conferences in the field of metastasis and the tumor microenvironment. He has served and is still serving on multiple study sections at the NIH, was the co-chair of the NCI Tumor Microenvironment Network and is a senior editor for Cancer Research for the Tumor Microenvironment-Immunology section. He has a solid record of accomplishment in education, mentoring and career development, being the PI on a longstanding (1991-present) NCI-funded T32 Program grant, and the chair of multiple mentoring committees of junior faculty members and postdoctoral trainees at USC and CHLA. He is the recipient of the 1991 H. Russell Smith Award for Innovation in Pediatric Biomedical Research, the USC Associates Award for Creativity in Research (2013) and the Richard Call Family Endowed Chair in Pediatric Research Innovation (2010).

Awards

USC: Associates Award for Creativity in Research , 2013

Children's Hospital Los Angeles: Richard Call Family Endowed Chair in Pediatric Research Innovation, 2010-pres

Children's Hospital Los Angeles: Associates & Affiliates Endowed Chair in Cancer Biology, 1994-pres

Fogarty : Senior International Fellowship, 1991-1992

Children's Hospital Los Angeles: H.Russell Smith Award for Innovation in Biomedical Research , 1991

Children's Hospital Los Angeles : Morris & Mary Press Humanism Award, 1987

American Cancer Society: Junior Faculty Career Development Award, 1982-1985

Catholic University of Louvain: SPECIA prize, 1973

Publications

The Tumor Microenvironment at a Turning Point Knowledge Gained Over the Last Decade, and Challenges and Opportunities Ahead: A White Paper from the NCI TME Network. Cancer Res. 2017 Mar 01; 77(5):1051-1059. View in: PubMed

More than the genes, the tumor microenvironment in neuroblastoma. Cancer Lett. 2016 Sep 28; 380(1):304-14. View in: PubMed

Fat, Calories, and Cancer. Cancer Res. 2016 Feb 1; 76(3):509-10. View in: PubMed

Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis. Int J Cancer. 2015 Aug 15; 137(4):797-809. View in: PubMed

Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing. Cancer Res. 2015 Aug 1; 75(15):2969-74. View in: PubMed

Small Molecule Inhibitors of Plasminogen Activator Inhibitor-1 Elicit Anti-Tumorigenic and Anti-Angiogenic Activity. PLoS One. 2015; 10(7):e0133786. View in: PubMed

MYCN-Dependent Expression of Sulfatase-2 Regulates Neuroblastoma Cell Survival. Cancer Res. 2014 Nov 1; 74(21):5999-6009. View in: PubMed

Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells. Mol Cancer Ther. 2014 Apr; 13(4):962-75. View in: PubMed

[Tumor microenvironment and therapeutic resistance process]. Med Sci (Paris). 2014 Apr; 30(4):445-51. View in: PubMed

Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res. 2013 Aug 15; 73(16):4965-77. View in: PubMed

Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. Cancer Res. 2013 Jul 1; 73(13):3852-64. View in: PubMed

Protumorigenic activity of plasminogen activator inhibitor-1 through an antiapoptotic function. J Natl Cancer Inst. 2012 Oct 3; 104(19):1470-84. View in: PubMed

Desmoplasia: a response or a niche? Cancer Discov. Desmoplasia: a response or a niche? Cancer Discov. 2012 Sep; 2(9):772-4. View in: PubMed

Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res. 2012 May 15; 72(10):2473-80. View in: PubMed

A galectin-3-dependent pathway upregulates interleukin-6 in the microenvironment of human neuroblastoma. Cancer Res. 2012 May 1; 72(9):2228-38. View in: PubMed

Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis. Cancer Biol Ther. 2012 May 1; 13(7):534-41. View in: PubMed

Synergistic Activity of Fenretinide and the Bcl-2 Family Protein Inhibitor ABT-737 against Human Neuroblastoma. Clin Cancer Res. 2011 Nov 15; 17(22):7093-104. View in: PubMed

A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study. Pediatr Blood Cancer. 2011 Aug; 57(2):275-82. View in: PubMed

Microsomal prostaglandin E synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice. Life Sci. 2011 Apr 11; 88(15-16):693-700. View in: PubMed

Stromelysin-1 (MMP-3) is a target and a regulator of Wnt1-induced epithelial-mesenchymal transition (EMT). Cancer Biol Ther. 2010 Jul; 10(2):198-208. View in: PubMed

Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Rev. 2010 Jun; 29(2):249-61. View in: PubMed

Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010 May; 46(7):1223-31. View in: PubMed

Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J Clin Invest. 2009 Jun; 119(6):1524-36. View in: PubMed

Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res. 2009 Jan 1; 69(1):329-37. View in: PubMed

Bone marrow microenvironment and tumor progression. Cancer Microenviron. 2008 Dec; 1(1):23-35. View in: PubMed

Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell. 2008 Oct 7; 14(4):324-34. View in: PubMed

Identification of galectin-3-binding protein as a factor secreted by tumor cells that stimulates interleukin-6 expression in the bone marrow stroma. J Biol Chem. 2008 Jul 4; 283(27):18573-81. View in: PubMed

The activity of zoledronic Acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. Cancer Res. 2007 Oct 1; 67(19):9346-55. View in: PubMed

Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. J Clin Invest. 2007 Sep; 117(9):2702-12. View in: PubMed

The cyclin-dependent kinase inhibitors p15INK4B and p21CIP1 are critical regulators of fibrillar collagen-induced tumor cell cycle arrest. J Biol Chem. 2007 Aug 17; 282(33):24471-6. View in: PubMed

Tumor progression and metastasis from genetic to microenvironmental determinants: a workshop of the tumor progression and metastasis NIH study section in honor of Dr. Martin L. Padarathsingh, May 31, 2006, Georgetown, Washington, DC. Cancer Biol Ther. 2006 Dec; 5(12):1588-99. View in: PubMed

Mechanisms of invasion and metastasis in human neuroblastoma. Cancer Metastasis Rev. 2006 Dec; 25(4):645-57. View in: PubMed

Multimodal imaging analysis of tumor progression and bone resorption in a murine cancer model. J Comput Assist Tomogr. 2006 May-Jun; 30(3):525-34. View in: PubMed

Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis. Cancer Res. 2006 Mar 1; 66(5):2691-9. View in: PubMed

Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev. 2006 Mar; 25(1):35-43. View in: PubMed

Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer. 2006 Feb; 42(3):310-8. View in: PubMed

Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen. J Biol Chem. 2005 Dec 2; 280(48):40187-94. View in: PubMed

Mechanisms of bone invasion and metastasis in human neuroblastoma. Cancer Lett. 2005 Oct 18; 228(1-2):203-9. View in: PubMed

Considering the critical interface between tumor cells and stromal cells in the search for targets for anticancer therapy. Cancer Cell. 2005 May; 7(5):408-9. View in: PubMed

The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependent. Cancer Res. 2005 Apr 15; 65(8):3200-8. View in: PubMed

Bone marrow mesenchymal stem cells provide an alternate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Res. 2005 Feb 15; 65(4):1129-35. View in: PubMed

Assessing growth and response to therapy in murine tumor models. Methods Mol Med. 2005; 111:335-50. View in: PubMed

Focus on the cell membrane: the need for dissociation and detachment in tumoral invasion. Cancer Biol Ther. 2004 Jul; 3(7):632-3. View in: PubMed

Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol. 2004 Apr; 164(4):1131-9. View in: PubMed

The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model. Cancer Res. 2004 Apr 1; 64(7):2328-32. View in: PubMed

Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation. J Biol Chem. 2004 Mar 5; 279(10):8592-601. View in: PubMed

Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res. 2004 Mar 1; 64(5):1675-86. View in: PubMed

TIMP-2 is released as an intact molecule following binding to MT1-MMP on the cell surface. Exp Cell Res. 2004 Feb 1; 293(1):164-74. View in: PubMed

Meeting report: Proteases, extracellular matrix, and cancer: an AACR Special Conference in Cancer Research. Cancer Res. 2003 Aug 1; 63(15):4750-5. View in: PubMed

Lytic bone lesions in human neuroblastoma xenograft involve osteoclast recruitment and are inhibited by bisphosphonate. Cancer Res. 2003 Jun 15; 63(12):3026-31. View in: PubMed

Gene therapy for hepatocellular carcinoma using non-viral vectors composed of bis guanidinium-tren-cholesterol and plasmids encoding the tissue inhibitors of metalloproteinases TIMP-2 and TIMP-3. Cancer Gene Ther. 2003 Jun; 10(6):435-44. View in: PubMed

Computerized quantification of tissue vascularization using high-resolution slide scanning of whole tumor sections. J Histochem Cytochem. 2003 Feb; 51(2):151-8. View in: PubMed

New approaches to the biology of melanoma: a workshop of the National Institutes of Health Pathology B Study Section. Am J Pathol. 2002 Nov; 161(5):1949-57. View in: PubMed

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