My research focuses on understanding the regulation of cell trafficking and cell metastasis in malignancies that disseminate in the bone marrow such as Multiple Myeloma (MM) and Waldenstrom Macroglobulinemia (WM). I specifically focus on the role of the malignant bone marrow niche in disease progression from early precursor conditions like MGUS/smoldering MM to overt MM. We use MM as a model of bone metastasis and dissemination.
MM is a plasma cell dyscrasia characterized by the presence of multiple myelomatous “omas” throughout the skeleton indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. Although the term “metastasis” is not commonly used to describe dissemination of hematological malignancies, my lab attempts to examine how MM can use a process of cell dissemination that is similar to cell trafficking of hematopoietic stem cell (HSCs) and cell metastasis in solid epithelial carcinomas. These studies can guide our understanding of the biological changes that occur during progression in MM.
The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed.
To better examine in vivo localization of MM cells into the different niches of the bone marrow, we developed an imaging model to determine cell-cell interaction of tumor cells with the vascular niche or endosteal niche. Our group has shown that MM cells could be seen interacting with the endothelium of the calvarial bone marrow vasculature within minutes after intravenous injection into the tail vein of SCID mice using intravital confocal microscopy. We are currently examining the role of the malignant bone marrow niche and its components including stromal cells, endothelial cells and immune cells in regulating clonal evolution and tumor dissemination using a novel bone metastasis model with rainbow fluorescent 15 clone cell lines. In addition, we developed a novel in vitro bone marrow niche 3D model system to perform high-throughput screens such as RNAi or CRISPR screens as well as drug screens to examine interactions of stromal cells, endothelial cells and tumor cells.
We used the chemokine SDF-1 and its receptor CXCR4 as a model of understanding migration, homing and egress of MM and WM cells into and out of the marrow. We examined mechanisms of cell trafficking through the CXCR4/SDF-1 axis and downstream signaling proteins including the PI3K/Akt axis and Rho/Rac signaling. In addition, we identified a critical role of integrins, selectins and cadherins in regulating MM cell trafficking in vitro and in vivo. Moreover, we showed that hypoxia regulates cell dissemination and metastasis in MM through activation of transcription factors that modulate epithelial-mesenchymal transition (EMT), a process similar to that observed in solid tumor metastasis. Our recent data shows that activating mutation in CXCR4 (WHIM) in 20-30% of patients with WM leads to cell dissemination and drug resistance in WM cells and can be used to determine extramedullary disease in WM and drug resistance to PI3K, mTOR and BTK inhibitors. In addition, CXCR4 over-expression MM cells show extramedullary involvement and enhanced EMT-like transcriptional regulation that can be inhibited by a novel CXCR4 antibody inhibitor. Based on these studies, we have developed clinical trials using CXCR4 inhibitors in MM.
Although preparation of the pre-metastatic niche has not been studied in MM, we recently showed that stromal cells present in contact with MM cells secrete exosomes that modulate the growth and dissemination potential of MM cells. Our study showed that MM derived bone marrow stromal cells release exosomes, which are transferred to tumor cells, thereby resulting in modulation of tumor growth in vivo. Studies to define tumor derived exosomes and their role in preparing the pre-metastatic niche in MM are underway.
The lab is currently focusing on multiple aspects of cell metastasis or cell dissemination in MM and WM as tumor models for cell metastasis to the bone marrow niches: We are examining 1) mechanisms of early cell dissemination such as EMT transition and its epigenetic regulation, 2) the role of circulating tumor cells in cell dissemination, 3) preparation of the metastatic niche, 4) factors regulator progression of micrometastasis in patients with MGUS to overt MM, 5) miRNA regulators of tumor dissemination and stromal/myeloma interaction for cell dissemination, 6) Mechanisms of cell dissemination in extramedullary MM, 7) the role of hypoxia/metabolomics in regulating cell dissemination and drug resistance in MM.
In addition, our laboratory research data has been rapidly translated to innovative investigator-initiated clinical trials. We have conducted over 10 phase I and II clinical trials. Our studies on MM cell trafficking have been translated to the first chemosensitization trials in patients with Multiple Myeloma. In addition, I am the co-leader of the first consortium of clinical trials for blood cancers in collaboration with the Leukemia and Lymphoma Society to form the Blood Cancer Research Partnership (BCRP), a consortium for innovative clinical trials of 11 community oncology sites coordinated by DFCI. Moreover, we are initiating a new center for Prevention of Progression in Blood Cancers (BCP2) where patients with precursor conditions such as MGUS, early MDS and early CLL will be monitored propsectively for clonal evolution during disease progression. Clinical trials and research efforst will be coordinated for patients seen in this clinic to develop therapeutic agents that can prevent/delay disease progression in these early malignant conditions.
In support of the academic mission of Harvard Medical School, I am strongly involved in the teaching and training of our Internal Medicine Residents and Hematology/Oncology Fellows. I regularly give teaching lectures for Internal Medicine residents during their rotations on the Leukemia service and on morning teaching rounds. In addition, I am involved in the teaching of Hematology/Oncology fellows on regular basis and their academic career development. In addition, I am a mentor of Harvard Medical School/MIT students, The Continuing Umbrella of Research Experiences (CURE) program students as well as multiple postdoctoral fellows and students.