Alana Welm

We initially discovered that the Macrophage Stimulating Protein (MSP)/RON pathway is sufficient for spontaneous metastasis to multiple organs in a mouse model. We also found that MSP/RON expression can stratify breast cancer patients into groups of high or low risk of relapse due to metastatic disease. We have since elucidated the molecular mechanisms of tumor and host RON signaling that contribute to metastasis in mouse models and human breast cancer. In lung metastasis, RON functions in these cells to suppress the anti-tumor immune response, and inhibition of RON boosts CD8+ cytotoxic T cell activity to block metastatic outgrowth. In bone metastasis, RON additionally functions through a novel mechanism in osteoclasts to remodel bone matrix, facilitating tumor growth. RON inhibitors can complement current therapeutic strategies, such as RANKL inhibition, to protect from osteolysis.

To address the need to model heterogeneous human breast cancers in vivo, our lab led some of the earliest efforts to develop patient-derived xenograft (PDX) models for breast cancer. Our first paper on this subject described a bank of orthotopic patient-derived breast cancer xenografts (PDX) and, more importantly, provided models for spontaneous metastasis of breast cancer to multiple organs as occurs in patients. We also published a comprehensive protocol paper that is used as a standard in the field. This work prompted significant interest in the fields of breast cancer, metastasis, personalized medicine, and drug validation - and we have shipped our models to >100 labs and pharmaceutical companies across the world. Besides the technical advance, our work also provided important conceptual advances, in particular, the discovery that positive engraftment of breast cancers is a prognostic indicator of poor survival; the ability to grow in the mouse parallels the ability to metastasize in the human. We have extended this work and recently described use of PDX and organoids for precision medicine in breast cancer