Shapiro, Lawrence

ABSTRACT Here, we show that cells expressing the adherens junction protein nectin-1 capture nectin-4-containing membranes from the surface of adjacent cells in a trans-endocytosis process. We find that internalized nectin-1–nectin-4 complexes follow the endocytic pathway. The nectin-1 cytoplasmic tail controls transfer: its deletion prevents trans-endocytosis, while its exchange with the nectin-4 tail reverses transfer direction. Nectin-1-expressing cells acquire dye-labeled cytoplasmic proteins synchronously with nectin-4, a process most active during cell adhesion. Some cytoplasmic cargo remains functional after transfer, as demonstrated with encapsidated genomes of measles virus (MeV). This virus uses nectin-4, but not nectin-1, as a receptor. Epithelial cells expressing nectin-4, but not those expressing another MeV receptor in its place, can transfer infection to nectin-1-expressing primary neurons. Thus, this newly discovered process can move cytoplasmic cargo, including infectious material, from epithelial cells to neurons. We name the process nectin-elicited cytoplasm transfer (NECT). NECT-related trans-endocytosis processes may be exploited by pathogens to extend tropism. This article has an associated First Person interview with the first author of the paper.

Abstract Rational: Poor prognosis epithelial-derived cancers often exhibit morphologic and molecular changes characteristic of an epithelial to mesenchymal transition (EMT). EMT markers are predominantly found in tumors with a basal-like phenotype. Increased expression of the mesenchymal cadherins N-cadherin and/or Cadherin-11 (CDH11) and decreased E-cadherin, have been associated with both EMT and tumor progression. Importantly, CDH11 is a therapeutic target in rheumatoid arthritis (RA), an inflammatory disease with properties often compared with cancer. As CDH11 antibody based therapeutics are in clinical trials for RA and we recently showed that the arthritis drug celecoxib has the structural potential to bind CDH11, there is a strong possibility that, if CDH11can be shown to drive malignant progression rather than simply be associated with it, therapeutic options may be rapidly developed. Results: We show that CDH11 is increased early in breast cancer and ductal carcinoma in-situ. CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors. CDH11 attenuation decreased proliferation and colony formation of breast, glioblastoma and prostate cancer cells. The arthritis drug celecoxib, which has characteristics consistent with CDH11 binding, an analogue without COX-2 inhibitory activity and other molecules that target CDH11, preferentially affect CDH11 positive cancer cells. Conclusion: Our work demonstrates that cadherin-11 is important for malignant progression, is a therapeutic target in several aggressive tumors and introduces an antibody, novel small molecules and an approved arthritis drug that inhibit its function with potential for rapid clinical translation. Citation Format: Shahin Assefnia, Sivanesan Dakshanamurthy, Jaime M. Guidry Auvil, Constanze Hampel, Panos Anastasiadis, Bhaskar Kallakury, Aykut Uren, David W. Foley, Milton Brown, Lawrence Shapiro, Michael Brenner, David Haigh, Stephen W. Byers. Cadherin-11, a common therapeutic target in poor prognosis malignancies and rheumatoid arthritis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A045.