Early induction of the Rho-GEF ECT2 drives MEK/ERK oncogenic signaling in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers because it is typically detected at an advanced stage, progresses rapidly, and resists current therapies. Consequently, early diagnostic biomarkers and novel therapeutic targets are urgently needed. Epithelial Cell Transforming Sequence 2 (ECT2) is a Rho family guanine nucleotide exchange factor that was originally identified as an oncoprotein and later shown to regulate cytokinesis. Here, we evaluated ECT2 expression in human PDAC and its functional requirement for transformed growth and tumorigenicity. We found that ECT2 expression is elevated early in PDAC tumorigenesis, remains high throughout progression, and correlates with poor patient survival. Furthermore, a significant pool of ECT2 is mis-localized in the cytoplasm of PDAC cells. Knockdown of ECT2 inhibited 3D-transformed growth, invasion, and in vivo tumor formation while having little impact on PDAC cell cytokinesis. Mechanistically, we found that ECT2 is required for activation of Rac1 and RhoA and downstream MEK/ERK and ROCK signaling, respectively. Consistent with these findings, analyses of PDAC patient datasets revealed a strong association between ECT2 expression and Rho GTPase as well as MEK/ERK and ROCK pathway signatures. Finally, genetic or pharmacologic targeting of ECT2 signaling enhanced PDAC cell sensitivity to MEK inhibition. Taken together, our data identify ECT2 as an early driver of PDAC transformation and highlight it as a promising therapeutic target.