Tumor Type-Specific Regulatory Core And Key Molecular Signatures Underlying E2F1-Mediated Epithelial ToMesenchymal Transition

Tumor metastasis continues to be the most significant problem in the field of cancer. Theincreasingly high rates of lethal outcome associated with tumor metastasis rely on the acquisitionof invasiveness and generation of chemo-resistance. Large number of clinical studies hints at thetranscription factor E2F1 that switches duties from tumor suppressor to promotor duringinvasiveness and metastasis, however the underlying mechanisms are largely unknown. Tounderstand how E2F1 interacts and regulate different molecules and how it mediates cancer relatedprocesses, we derived a detailed regulatory and functionally modularized E2F1 interaction mapfrom literatures and our own data. From the interaction map, we identified a large set of regulatorymotifs formed by feedback and feedforward loops which induce non-intuitive behavior. We furtheridentified the tumor-type and process specific most important motifs using a novel methodology formotif ranking. From top ranked motifs, we identified a regulatory core that controls the transitionfrom non-invasive to invasive phenotype. Based on the regulatory core, we derived a logic-basedmodel that accounts for the role of E2F1 in epithelial to mesenchymal transition in bladder andbreast cancer models Our simulation indicate that an invasive tumor phenotype in bladder cancer ismainly driven by E2F1 and FGFR1, while in case of breast cancer it is driven by E2F1 together withEGFR. These signatures were futher validated using invasive/ non-invasive bladder and breastcancer cell lines and also in the patient data. Further, we have identified novel pro-metastaticcofactors that interact with E2F1 and play a crucial role in switching E2F1 duties during diseaseprogression . Recently, using our computational methods, we screened FDA approved drug libraryfor the identification of potential therapeutic candidates that can inhibit E2F1-cofactor interactionsin order to develop novel anti-metastatic therapy. The therapeutic candidates were successfullyvalidated by our experimental partners both in in vitro and in vivo settings. Overall, our studycontributes towards a deeper understanding of the highly interconnected E2F1 signaling networkfor the development of tumor preventative measures and anti-metastatic therapies.