Figure 2.

Characteristics of FOXC1-overexpressing pro-metastatic cancers. 1. Plasticity whereby FOXC1+ cells undergo partial Epithelial-to-Mesenchymal Transition (EMT), and can revert back by undergoing a partial Mesenchymal-to-Epithelial Transition (MET). Detection of FOXC1+ E/M hybrid biphenotypic Circulating Tumor Cells (CTCs) in the peripheral blood of breast cancer patients provides clinical evidence supporting the occurrence of this phenomenon in vivo. 2. Chemoresistance to a variety of chemotherapeutic agents driven by FOXC1 has been described in multiple cancer types with varied mechanisms. 3. Radiation-induced adaptation and subsequent resistance has been described in two different types of cancer cell line models to be characterized by FOXC1 overexpression. 4. Stem cell pathway activation, particularly of the non-canonical variety has been described for NFĸB, Wnt, Hedgehog, PI3K/AKT/mTOR and TGFβ signaling pathways in cancer. Moreover, they all converge on FOXC1. This has led to the suggestion that combination therapy with two or more pathway inhibitor drugs may be necessary to block FOXC1-driven cancer metastasis. 5. Superenhancer-driven transcriptional addiction to FOXC1 mediated by CDK7 has been described in breast cancer and was shown to be effectively thwarted using a CDK7 inhibitor drug. 6. FOXC1 contributes to an immunosuppressive microenvironment by upregulating multiple immunosuppressive factors including HIF1α, CXCR4, CXCR1 and LOX1. This helps explain how the cancer stem cell phenotype helps evade immune detection, and how FOXC1+ cancers are a valid target for immunotherapy approaches like immune checkpoint inhibitors.