Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

Abstract

Metastasis accounts for more than 90% of cancer related mortality, thus the most pressing need in the field of oncology today is the ability to accurately predict future onset of metastatic disease, ideally at the time of initial diagnosis. As opposed to current practice, what would be desirable is that prognostic, biomarker-based detection of metastatic propensity and heightened risk of cancer recurrence be performed long before overt metastasis has set in. Without such timely information it will be impossible to formulate a rational therapeutic treatment plan to favorably alter the trajectory of disease progression. In order to help inform rational selection of targeted therapeutics, any recurrence/metastasis risk prediction strategy must occur with the paired identification of novel prognostic biomarkers and their underlying molecular regulatory mechanisms that help drive cancer recurrence/metastasis (i.e. recurrence biomarkers). Traditional clinical factors alone (such as TNM staging criteria) are no longer adequately prognostic for this purpose in the current molecular era. FOXC1 is a pivotal transcription factor that has been functionally implicated to drive cancer metastasis and has been demonstrated to be an independent predictor of heightened metastatic risk, at the time of initial diagnosis. In this review, we present our viewpoints on the master regulatory role that FOXC1 plays in mediating cancer stem cell traits that include cellular plasticity, partial EMT, treatment resistance, cancer invasion and cancer migration during cancer progression and metastasis. We also highlight potential therapeutic strategies to target cancers that are, or have evolved to become, “transcriptionally addicted” to FOXC1. The potential role of FOXC1 expression status in predicting the efficacy of these identified therapeutic approaches merits evaluation in clinical trials.

The Monocyte, a Maestro in the Tumor Microenvironment (TME) of Breast Cancer

“…Accordingly, FOXC1 is upregulated upon the sponging of miR-3607 [ 64 ]. The exact mechanisms of activity for FOXC1 were previously discussed in the referenced review [ 65 ].…”

Mesenchymal stem cells derived from patients with premature aging syndromes display hallmarks of physiological aging

“…Interestingly, most dDEGs correspond to biological pathways related to the development of the mesoderm, cartilage, ECM, and response to transcription factors, consistent with defects reported on these pathologies ( 12 , 16 , 17 , 20 , 21 ). Among dDEGs, we selected a list of genes corresponding to the identified biological pathways, including two collagens ( COL1A1 , COL1A2 ) and one transcription factor (TF) involved in the development of mesenchymal tissues, bone, skin, and the cardiovascular system, FOXC1 ( 50 , 51 ). We confirmed the constant down-regulation of these ECM proteins, specifically in cells producing progerin or the ∆35 isoform (HGPS and HGPS-L, respectively).…”

The Unholy Trinity- Cancer cell plasticity, drug resistance and therapeutic opportunities

“…Mutations in BRAF gene lead to alterations in the RAS-RAF-MEK-ERK pathway 10 which has a major role in developing drug resistance. A pivotal transcriptional factor named FOXC1 is a factor that mediated cancer cell plasticity and metastasis via partial EMT which in turn leads to drug resistance in the same and is regulated by this signaling pathway in breast cancer cells 20 .…”