Pleiotropic functions of FOXC2 in EMT, stem cells and breast cancer progression

点击翻译按钮获取中文摘要

Development of resistance to therapies, tumor relapse, and metastasis pose significant risks to breast cancer patients and are responsible for the majority deaths among these cancer patients. Recent studies have demonstrated that the developmental process is known as epithelial-mesenchymal-transition (EMT) as well as a subpopulation of cancer cells termed cancer stem cells (CSC), in these various processes. We and others have shown that the EMT program and stem cell properties are interconnected, and specifically, cancer cells are capable of acquiring stem cell attributes through the activation of EMT. This suggested that targeting EMT program may reduce the disease burden and will decrease death among cancer patients. However, the dearth of signaling pathways emanating from the tumor microenvironment capable of inducing EMT - including inflammatory cytokines and transforming growth factor β-1 (TGFβ1) makes it impossible to therapeutically target EMT. Cumulative studies from our laboratory over the last 9 years have resulted in the seminal identification of the transcription factor FOXC2, as a key player in metastasis and also as a common downstream effector of multiple EMT-signaling pathways and indispensable for the procurement of CSC properties. A characteristic feature of CSCs is their capability to self-renew via asymmetrical or symmetrical self-renewal type of cell divisions thereby enabling the continued existence and expansion of the CSC pool. The current proposal will systematically test the role of FOXC2 as a critical element of the molecular switch facilitating CSC self-renewal and expansion, and investigate if aberrant activation of FOXC2 leads to increase in CSC populations via Notch signaling, resulting in tumor progression and metastasis. We will use a combination of in vitro-, and in vivo tumor models, and patient-derived xenografts as well as genetically engineered mouse models to tease out this process. We will also examine the function of TGFβ1, a physiologically relevant inducer of EMT, in dictating FOXC2-induced CSC expansion. Also, we will evaluate FOXC2-regulated mitotic bookmarking in maintaining the identity of the CSCs following stem cell division. Finally, we will test select small molecule inhibitors capable of modulating FOXC2-function in selectively preventing CSC expansion during EMT. Significance: In summary, our proposal will not only help clarify the fundamental processes regulating CSC self-renewal and expansion of CSCs during EMT but will also contribute to designing novel strategies that would provide an opportunity to shift the balance of CSC towards more differentiated cells and exhaust therapy-resistant, metastasis-prone CSCs.