Research Overview
Our laboratory focuses on tumor microenvironment in cancer progression. Cancer is not only a disease of the genes, but the result of close interactions between genetically unstable malignant cells and non-transformed elements (cells, matrix proteins, soluble factors) that contribute to the formation of a tumor. These normal elements are not innocent bystanders, but actively influence cancer progression.
Our ultimate goal is to better understand the mechanisms of communication between tumor cells and their microenvironment, to identify specific targets for therapeutic intervention. Our laboratory performs fundamental cancer biology and pre-clinical experiments that will lead to the testing of specific agents targeting the tumor microenvironment in pediatric clinical trials.
Our laboratory is a member of the Cancer Program of the Cancer and Blood Disease Institute and The Saban Research Institute at Children's Hospital Los Angeles. We also work within the Tumor Microenvironment Program of the USC Norris Comprehensive Cancer Center of the Keck School of Medicine.
Role of the Tumor Microenvironment in Drug Resistance
Drug resistance is the major cause of failure to cure cancer. Whereas genetic alteration and genomic instability play an important role in drug resistance, there is now evidence that the tumor microenvironment can provide tumor cells with a sanctuary that allows them to escape the toxicity of drugs and to become resistant to therapies. This process is known as environment-mediated drug resistance (EMDR).
Our laboratory has identified an interleukin-6/STAT3 interactive pathway between tumor cells and bone marrow mesenchymal cells that promotes drug resistance in neuroblastoma. Neuroblastoma cells do not make IL-6 and do not have constitutive activation of STAT3 but when in the presence of bone marrow-derived mesenchymal cells or monocytes, they stimulate the production of IL-6 and the soluble agonistic receptor for IL-6 by these normal cells. IL-6 then induces in tumor cells the expression of survival factors that protect tumor cells from drug induced apoptosis in a STAT3 dependent manner (Ara et al., Cancer Research 2009). We are now exploring in preclinical models of neuroblastoma whether inhibitors of JAK2/STAT3 can prevent drug resistance and increase the therapeutic response of neuroblastoma to cytotoxic agents.
Contribution of Bone Marrow Derived Mesenchymal Cells to Cancer Progression
The bone marrow is a unique microenvironment for cancer cells as it provides a niche for dormant tumor cells and is a common site of metastasis in many cancers including neuroblastoma. Our laboratory found that mesenchymal cells in the bone marrow play an important contributory role in neuroblastoma bone metastasis by being a source of IL-6 which stimulates bone degradation by osteoclast (Sohara et al., Cancer Research 2003 and 2005). We also showed that blocking osteoclast activity with bisphosphonates such as zoledronic acid (ZA) significantly reduces osteolysis in preclinical models of bone invasion (Peng et al., Cancer Res 2007).
This led to the development of a phase 1 clinical trial that demonstrated the safety and efficacy of ZA in patients with metastatic neuroblastoma (Russell et al., Pediatr Blood Cancer 2011). We have also obtained preliminary evidence that mesenchymal cells are recruited by primary tumors where they may create the same protective microenvironment.
Our current work focuses on examining mechanisms by which tumor cells communicate with mesenchymal cells and how exosomes play a critical role in this aspect. We are also investigating the role of osteoblasts in neuroblastoma bone metastasis.
Protease and Protease Inhibitors in Cancer
Many cancer cells secrete proteases that degrade the extracellular matrix and process growth factors, membrane associated proteins and cytokines. Among these proteases is plasminogen activator (PA), a serine protease that is overexpressed by transformed cells and many malignant cells. Somewhat paradoxically, the inhibitor of PA, the plasminogen activator inhibitor-1 (PAI-1) is also overexpressed in more aggressive forms of cancer. In our laboratory we have described a novel mechanism by which PAI-1 acts as a proangiogenic molecule promoting the vascularization of tumors that explain its paradoxical elevation in aggressive forms of cancer (Bajou et al., Cancer Cell 2008).
More recently we reported that PAI-1 protects tumor cells from spontaneous apoptosis and that in a total absence of host and tumor-derived PAI-1 tumors do not form, raising the possibility that PAI-1 may play a role in controlling tumor dormancy (Fang et al., JNCI 2012).
Key Findings
- Discovery of a novel inhibitor of matrix metalloproteinases and of its role in inhibition of tumor cell invasion (Boone et al., PNAS 1990; DeClerck et al., Cancer Research 1991).
- Bone marrow mesenchymal cells contribute to neuroblastoma progression by promoting osteolysis and drug resistance (Sohara et al., Cancer Res. 2005 and Ara et al., Cancer Research 2009).
- PAI-1 is a proangiogenic factor by protecting endothelial cells from Fas-L/Fas (Bajou et al., Cancer Cell 2008; Fang et al., JNCI 2012).
Research Support
- Center for Environment-Mediated Drug Resistance in Pediatric Cancer
This multiple PI project would create a center to conduct fundamental inquiries on mechanisms responsible for environment-mediated drug resistance.
Principal Investigator: Yves A. DeClerck, MD
Agency: National Cancer Institute
Type: U54 (CA163117-02) Period: Sept. 1, 2011 – Aug. 31, 2016 - Biology and Therapy of High Risk Neuroblastoma
Principal Investigator: Robert C. Seeger, MD
Agency: National Cancer Institute
“Biology of Neuroblastoma Bone Metastasis”,
Project 1: This project examines the role of the bone marrow microenvironment in neuroblastoma bone metastasis.
Principal Investigator: Yves A. De Clerck, MD
Type: PO1 (CA84103-13) Period: Apr. 01, 2000 – May 31, 2015 - Environment-Mediated Drug Resistance in Neuroblastoma
The studies are a collaborative effort between 2 PIs with complementary expertise. They aim to demonstrate the therapeutic efficacy of targeting the IL-6/S1PR1/JAK2/STAT3 axis in inhibiting bone marrow driven EMDR.
Principal Investigator: Yves A. DeClerck, MD
Agency: Department of Defense
Type: (PR110259) Period: July 01, 2012 – June 30, 2015 - Training in Basic Research in Oncology
This training grant supports the training of MD postdocs in cancer research.
Principal Investigator: Yves A. DeClerck, MD
Agency: National Cancer Institute
Type: T32 (CA09659-18) Period: Sept. 1, 1991 – Aug. 31, 2015 - Norris Cancer Center Core Grant
This cancer center grant provides salary support to Dr. DeClerck, who is the Co-leader of the Tumor.
Microenvironment Program.
Principal Investigator: Stephen B. Gruber, MD, PhD, MPH
Agency: National Cancer Institute
Type: P30 (CA14089) Period: Apr. 1, 1980 – Nov. 30, 2015 - Los Angeles Basin Clinical and Translational Science Institute
Dr. DeClerck is the Co-Director of the Center for Translational Science
Principal Investigator: Thomas Buchanan, MD
Agency: National Institutes of Health
Type: UL1 (RR031986-03) Period: July 1, 2010 – June 30, 2015 - Children’s Hospital Los Angeles Child Health Research Career Development Award
This is a training grant for junior faculty in the Department of Pediatrics to provide focused mentoring, protected times and research funding to promising junior faculty physician scientists engaged in basic research targeted towards clinical pediatric diseases.
Principal Investigator: D. Brent Polk, MD
Program Co-Director: Yves A. DeClerck
Agency: National Institutes of Health
Type: 2 K12 HD052954-07A1 Period: Dec. 1, 2011 – Nov. 30, 2016
