Role of Osterix+ Osteolineage Cells in Primary and Metastatic Breast Cancer

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ABSTRACT In order to survive, grow and metastasize, tumors need the support of a favorable host environment. Local changes in normal cells in close proximity to a developing tumor can create a favorable tumor micro-environment (TME) that is necessary for tumor growth. Mesenchymal populations, including cancer-associated fibroblasts (CAFs), secrete pro- tumorigenic and immune suppressive factors, and produce extracellular matrix to create a stiffer, tumor-conducive soil. Several CAF subsets with specific functions have been identified, however, whether distinct CAF subsets derive from the same progenitor that acquire functional specificity during tumor progression or from different progenitors committed to give rise to a specific CAF population, is under investigation. We recently made the unexpected observation that cells expressing bone osteolineage marker Osterix (Osx) are present in the TME of tumors outside the bone and support tumor growth. In adult animals, Osx is expressed by committed osteoblasts (OB) and drives their differentiation. Surprisingly, we detected Osx in stromal cells, isolated from various breast cancer tumors, expressing CAF and OB makers, and in the tumor-associated stroma of patients with breast carcinomas. Co-injection of Osx+ cells with tumor cells enhance tumor growth. Importantly, Osx expression correlates with poor prognosis in breast cancer. Based on these rather unexpected findings, we hypothesize that bone-derived osteolineage Osx+ cells represent a novel subset of tumor infiltrating stromal populations contributing to tumor progression and CAF diversity. Aim 1 will determine the functional relevance of Osx+ cells in the TME and pre-metastatic sites; Aim 2 will determine the origin of Osx+ cells in the TME and pre-metastatic sites. This information will broaden the concept of cellular heterogeneity within the TME and offer a new platform for targeting the stroma with the purpose of inhibiting tumor growth.