Elucidating the molecular mechanisms of metastasis organ tropism

PROJECT SUMMARY The molecular and cellular biology of metastasis is multifactorial, and this complexity contributes to the challenge of treating patients with metastatic disease. One of the challenges of metastasis biology is to determine why certain tumor subtypes have preferential sites of metastasis: e.g. TNBC/Basal-like breast cancers tend to metastasize to visceral organs, while ER-positive/Luminal breast cancers tend to metastasize to the bone. In addition, once metastases are established at a distant site, it is critical to understand how these tumors interact with the local microenvironment and identify the tumor-to-organ crosstalk might be occurring to sustain tumor growth. This proposal aims to address these questions by utilizing a comprehensive and carefully curated dataset of paired human primary tumors and metastasis samples, and a similar paired Genetically Engineered Mouse Mammary tumor models dataset. We seek to identify the molecular determinants of lung and liver organ-specific metastasis using supervised learning approaches and this extensive human and in vivo mouse models breast cancer data set. Lastly, using spatial transcriptomics, we will characterize unique organ microenvironments to identify critical crosstalk that contributes to sustained tumor growth, thus possibly offering a new means for therapeutic interventions.