Abstract / Summary
Metastasis is responsible for most cancer-related deaths; yet there are no therapies specifically targeting any aspect of the metastatic cascade. Recently, metastatic success has been linked to the ability of cancer cells to engage in cooperative interactions. Although such interactions add to the complexity of cancer, they also represent potential vulnerabilities that can be exploited therapeutically. Using an in vitro breast cancer model-system, we previously showed that a highly metastatic clone (MDA-MB-231) can co-opt – via the TGFβ1 pathway, a weakly metastatic clone (MCF7) into expressing a more migratory/invasive behavior that ultimately also benefits the aggressive clone (a “help me help you” strategy). Here, we investigated the pathways involved in this interaction, with the goal of identifying components that can be targeted with available drugs. To do so, we performed a series of transcriptomic analyses combined with experimental blocking of the pathways identified through transcriptomic profiling. In addition to TGFβ, we found several pathways that work in concert to increase the migration of MCF7 in response to the conditioned medium (CM) from MDA. These include: the EGFR/ERBB pathway, the MAPK/ERK cascade, the AP-1 transcription complex and the CTGF/Integrin/FAK axis. Blocking each of these pathways (including with approved drugs such as Erlotinib, Neratinib, Selumetinib and Defactinib) resulted in the complete suppression of the CM-induced migration of MCF7. These findings raise the possibility that analogous cooperative interactions occur in vivo and targeting these conserved signalling pathways with already available drugs may represent an effective strategy to disrupt cooperative interactions and slow down the metastatic process.