When cancer metastasizes to bone, considerable pain and deregulated bone remodeling occurs, greatly diminishing the possibility of cure. Metastasizing tumor cells mobilize and sculpt the bone microenvironment to enhance tumor growth and to promote bone invasion. Basic findings of tumor–bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases. Our lab focuses on targeting the Hedgehog (Hh) pathway. Hh pathway activation through overexpression of Hh ligand Sonic hedgehog (Shh) or mutations in many Hh signaling genes (smo, ptch1, gli1, gli2) have been implicated in development and progression of numerous epithelial cancers such as breast, skin, esophagus, stomach, pancreas, liver, lung and prostate. Furthermore, the growth of many human tumors is supported by Hh pathway activity in stromal cells. We hypothesize that inhibition of the Hh pathway can reduce tumor burden in bone, regardless of tumor Hh responsiveness, through effects on tumor cells, osteoclasts and other immune cells within the tumor microenvironment, making Hh a promising therapeutic target for cancer and bone metastases.
Multiple Sclerosis (MS) is thought to be an autoimmune disease where immune cells migrate into the central nervous system (CNS) and attack myelin, a dielectric sheath that wraps large axons. Although autoreactive T cells have traditionally been thought to be the key players in MS, recent studies have indicated that B cells also play a critical role in the pathogenesis of MS. B cells and oligoclonal immunoglobulins have been found in MS lesions and MS cerebrospinal fluid (CSF), respectively. Evidence also suggests that B cell mediated effects on disease expression may be independent of antibodies. B cells are thought to aggregate into ectopic lymphoid structures, and several lymphoid chemokines including CXCL13, CCL19 and CXCL12 have been implicated in the formation of such ectopic lymphoid aggregations. These chemokines have been found within MS lesions and in CSF. Moreover, therapeutic agents for MS that target B cells are also associated with a decline in CXCL13 and CCL19 within MS CSF and serum. Antigen presentation by B cells is required for the development of a T cell response, and we hypothesize that the lymphoid chemokine CXCL13 orchestrates the interactions between T and B cells within the CNS during MS. To test this hypothesis we are using a murine model for MS that leads to a relapsing-remitting disease, which is the most common form of MS in human subjects. Using antibodies that neutralize CXCL13, we are studying the effects of this neutralization on the recruitment and interaction of T and B cells. Understanding the role of CXCL13 in MS and how B cells enter and induce disease within the CNS will help us identify drug targets that can be used to stop the recurrent attacks of MS and progression of the disease.