The intestinal epithelial cells (IECs) lining the lumen of the colon are normally attached to a complex matrix of proteins known as the Basement Membrane (BM). When this attachment to the BM is lost or prevented, normal IECs will undergo apoptosis (or “cell suicide”), in a process known as anoikis (in ancient Greek, “homelessness”) . On the other hand, colon cancer cells are not only able to survive in the absence of proper attachment to the BM but can also proliferate and invade surrounding and distant tissues, giving rise to metastases, i.e. malignant cells are by definition resistant to anoikis. Therefore, understanding the molecular mechanisms that regulate the execution of anoikis of IECs, and how these mechanisms are altered in colorectal tumor cells, may help us exploit this fundamental difference between normal and tumor cells and develop new therapies for the treatment of colon cancer. In fact, therapies based on restoring and/or enhancing the sensitivity of colorectal cancer cells to anoikis are expected to be fairly specific, since normally attached IECs would not be targeted by them, which would result in low toxicity. One of the molecules whose function is most frequently altered (activated) in colon cancer patients is the non-receptor tyrosine kinase c-SRC . In the last few years, we have been studying some of the molecular mechanisms by which activated c-SRC can prevent anoikis in IECs. For that purpose, we use the previously characterized model cell line IEC18, which had been transformed with the oncoprotein v-SRC (a constitutively active mutant of SRC) . These v-SRC-transformed cells show levels of SRC kinase activity that are several times higher than those in the parental IEC18 cells (Fig.1A). Importantly, the relative difference in the levels of c-SRC kinase activity found between colorectal cancer samples and surrounding normal stroma is very similar to that in our model . Even though our previous studies confirmed early observations that linked v-SRC to resistance to anoikis and provided some cues on the molecular mechanisms involved in the process , they did not address whether physiological levels of c-SRC activity could also protect cells from anoikis. If resistance to anoikis were a “gain of function” phenotype related to carcinogenic hyperactivation of c-SRC, the inhibition of c-SRC activity as a pro-anoikic approach would only be applicable in cases that present such hyperactivation. Conversely, if normal c-SRC activity levels are also involved in regulating anoikis, then c-SRC could represent a more general target to enhance anoikis in detached cells. To start investigating this issue, we first analyzed the behavior of endogenous cSRC activity in IEC18 cells in response to detachment. We found that after long periods in suspension culture ( 6 hours), the activity levels of c-SRC were significantly reduced (Fig 1A). Thus, we were able to show there is a correlation between a decrease in SRC activity and anoikis, which led us to hypothesize that detached IECs might induce their own demise at least in part because they lose their c-SRC activity. One of the obvious implications of such hypothesis is that any intraor extracellular process that inhibits the detachment-induced decrease in the activity of c-SRC would make the cells resist anoikis, even if it did not activate c-SRC activity above its basal levels in attached cells. Moreover, inhibition of c-SRC activity in these cases would, in principle, lead to an enhanced sensitivity to anoikis. We then decided to set out and explore this possibility in other well-established models of resistance to anoikis in intestinal epithelial cells. At the time, we were trying to understand the molecular mechanisms by which the Epidermal Growth Factor Receptor (EGFR) inhibits anoikis in IECs. The EGFR is a membrane associated receptor tyrosine kinase (RTK), which has been repeatedly associated with an anoikis resistant phenotype in diverse cellular systems.