Abstract IA08: Developmental insights into breast cancer intratumoral heterogeneity

Abstract

Abstract Breast cancer is no longer considered a single disease, but instead is made up of multiple subtypes with genetically and epigenetically heterogeneous tumors composed of numerous clones. Both the hierarchical cancer stem cell and clonal evolution models have been invoked to help explain this intratumoral heterogeneity. Several recent studies have helped define the functional interactions among the different cellular subpopulations necessary for the evolution of this complex ecosystem. These interactions involve paracrine interactions that include locally acting Wnt family members, reminiscent of the signaling pathways important for normal mammary gland development and stem cell self-renewal. For example, mammary gland stem cell self-renewal is regulated by paracrine signaling involving Wnt4 and RSPO1 secreted by differentiated mammary luminal cells under the influence of systemic steroid hormones. Furthermore, interactions between non-canonical and canonical Wnt pathways play an important role in mammary gland development and cell fate determination [1]. Using a genetically engineered p53 null triple negative breast cancer model, we described a novel feedback loop in which the breast cancer stem cells(CSC) function through the action of paracrine mediators secreted by the CSC progeny[2], similar to what is observed in the normal mammary gland. We demonstrated the existence of cross-talk between tumor cells via Wnt2, Cxcl12 and IL6 signaling, indicating the non-cell-autonomous properties and importance of cooperativity between tumor subpopulations in tumor initiation and progression. Ligands expressed in the mesenchymal progeny cells produced through the asymmetric division of CSCs interacted with receptors on the CSCs. Knockdown of the ligands in the mesenchymal cells and their respective receptors in the CSCs resulted in decreased mammosphere formation in co-cultures. Furthermore, knockdown of Wnt 2 in the mesenchymal cells resulted in increased tumor latency when limiting numbers of CSCs were transplanted into the cleared mammary fat pad. The functional interactions between CSCs and mesenchymal population of cells may provide an improved niche microenvironment, especially for those tumors initiated from extremely low numbers of the CSCs. These studies indicate that similar regulatory mechanisms may exist for the maintenance of both normal and tumor stem cells with respect to their symmetric and asymmetric division. A better understanding of these interactions, especially in the metastatic setting, will be important for the development of improved combinatorial therapies designed to prevent relapse and to ultimately decrease mortality.