@article{3bd36978dff040498b6579ca407e5caa,
title = "Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth",
abstract = "ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of fulllength ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2mRNAabundance and associated with APC tumorsuppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a KrasG12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells.",
author = "Cook, {Danielle R.} and Melissa Kang and Martin, {Timothy D.} and Galanko, {Joseph A.} and Loeza, {Gabriela H.} and Trembath, {Dimitri G.} and Verline Justilien and Pickering, {Karen A.} and Vincent, {David F.} and Armin Jarosch and Philipp Jurmeister and Waters, {Andrew M.} and Hibshman, {Priya S.} and Campbell, {Andrew D.} and Ford, {Catriona A.} and Keku, {Temitope O.} and Yeh, {Jen Jen} and Lee, {Michael S.} and Cox, {Adrienne D.} and Fields, {Alan P.} and Sandler, {Robert S.} and Sansom, {Owen J.} and Christine Sers and Antje Schaefer and Der, {Channing J.}",
note = "Funding Information: The study was funded in part by National Institute of Health grants CA129610 and CA67771 (to C.J. Der), CA199235 (to C.J. Der and A.D. Cox), CA140424 (to J.J. Yeh), CA93326 and DK034987 (to R.S. Sandler and T.O. Keku), CA204938 (to V. Justilien) and CA081436, CA180997, and CA151250 (to A.P. Fields). D.R. Cook was supported by a National Institutes of Health training grant (T32CA071341) and an F31 predoctoral fellowship (CA159821). C.J. Der was also supported by a Pancreatic Cancer Action Network-AACR RAN grant. C.J. Der and C. Sers were supported by an Einstein Foundation grant (EVF-BIH-2018-431). C.J. Der and A.D. Cox were supported by funds provided by the Julie M. Brown and Christina Gianoplus Colon Cancer Foundation. The study was also supported by Cancer Research UK core funding to the Beatson Institute (A17196) and to O.J. Sansom (A21139). O.J. Sansom was also supported by an ERC Starter Grant (311301). A.M. Waters was funded by the American Cancer Society grant PF-18-061-01. The authors thank the Translational Pathology Laboratory (TPL) at UNC for staining, Aperio algorithm and analysis, and Carolyn Suitt and Nikki McCoy for TMA sectioning. They thank the UNC Microscopy Services Laboratory (MSL) and the UNC flow cytometry core facility for their assistance. Funding Information: M.S. Lee reports grants, personal fees, and nonfinancial support from Pfizer, Bristol Myers Squibb, and grants and nonfinancial support from Amgen, Genentech/ Roche, grants from Exelixis, grants from Rafael Pharmaceuticals, and grants and nonfinancial support from EMD Serono outside the submitted work. A.D. Cox reports personal fees from Mirati Therapeutics, Eli Lilly, and grants from NIH, Pancreatic Cancer Action Network-AACR RAN M. Brown and Christina Gianoplus Colon Cancer Foundation, and SpringWorks Therapeutics during the conduct of the study; personal fees from Mirati Therapeutics and grants from SpringWorks Therapeutics outside the submitted work. A.P. Fields reports grants from NIH/NCI during the conduct of the study. O.J. Sansom reports grants from Novartis, Astra Zeneca, Cancer Research Technology, and Redex outside the submitted work. C.J. Der reports grants and personal fees from Mirati Therapeutics, and grants from SpringWorks Therapeutics, and personal fees from Revolution Medicines, Eli Lilly, Anchiano Therapeutics, grants and personal fees from Deciphera Therapeutics, and personal fees from Jazz Therapeutics, Ribometrix, Sanofi, Turning Point Therapeutics, and grants from National Institutes of Health, Pancreatic Cancer Action Network-AACR, Einstein Foundation, and Julie M. Brown and Christina Gianoplus Colon Cancer Foundation during the conduct of the study; grants and personal fees from Mirati Therapeutics, grants from SpringWorks Therapeutics, and personal fees from Revolution Medicines, Eli Lilly, Anchiano Therapeutics, grants and personal fees from Deciphera Therapeutics, and personal fees from Jazz Therapeutics, Ribometrix, Sanofi, and Turning Point Therapeutics outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = jan,
day = "1",
doi = "10.1158/0008-5472.CAN-20-4218",
language = "English (US)",
volume = "82",
pages = "90--104",
journal = "Cancer Research",
issn = "0008-5472",
number = "1",
}