Trop-2, Na+/K+ ATPase, CD9, PKCα, cofilin assemble a membrane signaling super-complex that drives colorectal cancer growth and invasion

Emanuela Guerra, Valeria Relli, Martina Ceci, Romina Tripaldi, Pasquale Simeone, Anna Laura Aloisi, Ludovica Pantalone, Rossana La Sorda, Rossano Lattanzio, Andrea Sacchetti, Kristina Havas, Simone Guarnieri, Daniele Vergara, Isabelle Fournier, Michel Salzet, Nicola Tinari, Mauro Piantelli, Marco Trerotola*, Saverio Alberti

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
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Abstract

Trop-2 is a transmembrane signal transducer that is overexpressed in most human cancers, and drives malignant progression. To gain knowledge on the higher-order molecular mechanisms that drive Trop-2 signaling, we applied next-generation sequencing, proteomics, and high-resolution microscopy to models and primary cases of human colorectal cancer (CRC). We had previously shown that Trop-2 induces a Ca2+ signal. We reveal here that Trop-2 binds the cell membrane Na+/K+-ATPase, and that clustering of Trop-2 induces an intracellular Ca2+ rise followed by membrane translocation of PKCα, which in turn phosphorylates the Trop-2 cytoplasmic tail. This feed-forward signaling is promoted by the binding of Trop-2 to the PKCα membrane-anchor CD9. CRISPR-based inactivation of CD9 in CRC cells shows that CD9 is required by Trop-2 for recruiting PKCα and cofilin-1 to the cell membrane. This induces malignant progression through proteolytic cleavage of E-cadherin, remodeling of the β-actin cytoskeleton, and activation of Akt and ERK. The interaction between Trop-2 and CD9 was validated in vivo in murine models of CRC growth and invasion. Overexpression of the components of this Trop-2-driven super-complex significantly worsened disease-free and overall survival of CRC patients, supporting a pivotal relevance in CRC malignant progression. Our findings demonstrate a previously unsuspected layer of cancer growth regulation, which is dormant in normal tissues, and is activated by Trop-2 in cancer cells.

Original languageEnglish
Pages (from-to)1795-1808
Number of pages14
JournalOncogene
Volume41
Issue number12
DOIs
Publication statusPublished - 18 Mar 2022

Bibliographical note

Funding Information:
We thank G. Vacca, F. Dini, E. Eleuterio, and S. Angelucci for help during the course of this work. We also thank C. Berrie for language editing of the paper.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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