1. Mechanisms by which MSP promotes escape of cancer cells from the primary tumor.
Our data suggest that MSP recruits and activates macrophages in the tumor environment, which in turn invoke migratory and invasive behavior on the tumor cells. We are identifying the critical signals that mediate the macrophage:tumor cell interactions downstream of MSP in vitro and in vivo.
2. Mechanisms by which MSP preferentially induces metastasis to bone.
We observed that MSP greatly facilitates metastasis of breast cancer to bone and causes 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.
3. Preclinical 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 3D culture and in vivo.
4. Development of better mouse models for preclinical drug testing for breast cancer.
We have successfully generated novel models that allow study of spontaneous metastasis of mouse mammary tumors. In collaboration with surgeons and pathologists at the Huntsman Cancer Institute Hospital, we are now moving to the next step, generating in vivo models of each of the five subtypes of breast cancer, by using new approaches to graft 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 individualized medicine, whereby a patient will receive a treatment based on the specific phenotype and genotype of their tumor.