Grant: CIHR Fellowship

Cancer is an interactive multi-cell, multi-tissue lesion dynamically linked to the stroma by signaling networks that regulate gene and protein expression, and post-translational modifications within the tumor and microenvironment. By the irreversible processing of bioactive proteins and signaling molecules, proteases modulate angiogenesis, growth, invasion, metastasis, and phenotypic evolution of cancer cells together with micro-environmental and host defense responses. Pioneering work by our lab on the proteomics of Matrix Metalloproteinases (MMPs) has identified and validated a myriad of new bioactive protein substrates in human breast cancer cells. It also revealed new roles for MMPs other than matrix degradation that may also account for the side effects arising from anticancer MMP inhibitor drugs. However, the protease repertoire-the degradome activity profile, and key substrates in breast cancer metastases remain unknown. Using our protease and inhibitor oligonucleotide microarray, the CLIP-CHIP, the protease transcriptome of the metastatic versus primary breast cancer tumors will be compared. To validate the breast cancer transcriptome, quantitative proteomics will be utilized to compare breast cancer metastases with primary tumors in mouse models. Cell membrane receptors, matrix proteins, signaling molecules, chemokines and proteases that are essential for the establishment and evolution of breast carcinoma metastases in bone, liver and lung will be identified in these proteomes by absolute quantitation isotope-labeled and tandem mass spectrometry. Key mediators will be mechanistically validated for cellular, transcriptome, and proteome responses in cell culture. Elucidating the key proteomic and degradomic features of metastases and primary breast carcinomas will reveal the mechanistic basis for organ trophism, metastases evolution, immune cell evasion and drug resistance, thereby identifying molecular targets to treat breast cancer metastases.