Death from breast cancer is largely attributed to metastasis—when the disease spreads to other tissues. In order to metastasize, cancer cells must be able to invade the local tissue, escape from the primary site, enter into and survive in the bloodstream or lymphatic system, pass from the blood vessels into other organs, and adapt to or modify the new site to create a new tumor. The molecular mechanisms used by tumor cells to facilitate metastasis are largely unknown, as are the processes by which our normal, healthy cells paradoxically support tumor growth and metastasis. Our research focuses on better understanding the tumor-host interactions that facilitate metastasis, with the ultimate goal of discovering new, improved cancer therapies.
The research in our laboratory is focused on the mechanisms of breast tumorigenesis and metastasis. Despite the fact that death from breast cancer is largely attributed to metastasis, we still don’t understand the mechanisms governing this complicated process, and there are currently no drugs designed specifically to block or prevent metastasis. Thus, a key challenge is to understand the molecular mechanisms by which each step of metastasis occurs, and then to identify therapeutic targets that prevent metastasis.
We have developed new, complementary in vitro and in vivo approaches to gain a better understanding of breast tumorigenesis and metastasis. We developed a new model system to efficiently study breast cancer and metastasis in mice without generation of transgenic animals. Using these methods, we discovered that macrophage stimulating protein (MSP) is an important facilitator of breast cancer metastasis. Our current areas of study are described below:
Mechanisms by which MSP promotes escape of metastatic cancer cells from the immune system. We are identifying the critical signals that mediate the macrophage:tumor cell interactions downstream of MSP and whether inhibition of the pathway can reduce or block metastasis in mouse models.
Mechanisms by which MSP preferentially induces metastasis to bone. We observed that MSP facilitates metastasis of breast cancer to bone and induces osteolysis, a common problem in human breast cancer. Our data suggest that MSP promotes bone metastasis by activating osteoclasts and causing bone resorption, which promotes further tumor growth. We are now identifying important downstream effectors of MSP that promote tumor growth in bone.
Pre-clinical studies of MSP inhibitors for treatment of metastatic breast cancer. Our studies showed that MSP not only promotes metastasis in mouse models of breast cancer, but also is significantly associated with metastasis and death in human breast cancer. We are currently testing inhibitors of the MSP signaling pathway in mouse models for efficacy in blocking or reducing metastasis. We are also testing these inhibitors on primary human breast cancer cells in patient-derived tumor grafts or xenografts (PDX).
Development of better mouse models for pre-clinical drug testing for breast cancer. In collaboration with surgeons and pathologists at the Huntsman Cancer Hospital, we have generated PDX (patient derived xenograft) models of several subtypes of breast cancer models of several subtypes of breast cancer, by directly grafting primary human breast tumors into mouse mammary glands. This will allow direct testing of new drugs for breast cancer in vivo, and should contribute to the evolution of personalized medicine, whereby a patient could receive a treatment based on the specific phenotype, genotype, and drug responsiveness of their tumor.
Deciphering the epigenetic programs that drive metastasis.We recently reported an epigenetic reprogramming pathway that is required for breast cancer metastasis. Our data shows that RON/MSP enhances metastasis of breast cancer xenografts by reprogramming DNA methylation at specific target genes. Future studies will address how aberrant DNA methylation is targeted to particular loci and which aberrantly regulated loci function in metastasis. In addition, we are studying the role of chromatin remodeling and histone modifications that may promote metastasis, as well as developing clinical strategies to provide more effective approaches to prevent or treat metastasis.