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

Oncogene volume 41, pages 1795–1808 (2022)Cite this article

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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.

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Fig. 1: Trop-2 induces intracellular Ca2+ rise through Na+/K+-ATPase.
Fig. 2: The Trop-2 cytoplasmic tail is required for PKCα recruitment to the cell membrane but not for intracellular Ca2+ rise.
Fig. 3: The Trop-2/PKCα feed-forward signaling.
Fig. 4: Trop-2 modulates cytoskeletal dynamics and interacts with CD9 at the cell membrane.
Fig. 5: CD9 is an obligate mediator of Trop-2 signaling.
Fig. 6: The Trop-2-centered growth control module.
Fig. 7: Expression of the Trop-2-driven super-complex correlates with the clinical outcome of patients with CRC.

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Acknowledgements

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.

Funding

Italian Ministry of Health (RicOncol RF-EMR-2006-361866), Italian Ministry of Development—FESR 2016–2018. SSI000651, art. 69 Reg. (CE) n. 1083/2006 and Reg. (CE) n. 1828/2006, Region Abruzzo (POR FESR 2007–2013: Activity 1.1.1 line B) C78C14000100005, Oncoxx Biotech, Italy and Marie Curie Transfer of Knowledge Fellowship—EC VI Framework Program (Contract 014541) to SA. Programma Per Giovani Ricercatori “Rita Levi Montalcini”, Italian Ministry of University and Research (Grant PGR12I7N1Z) to MT. EG is an inventor in patents WO201687651 and WO201784763, and a partner in Mediterranea Theranostic Srl. MT is an inventor in patent WO201784763. SA is an inventor in patents WO201089782, WO201687651, and WO201784763, and is founder and CEO of Oncoxx Biotech Srl and Mediterranea Theranostic Srl. VR was an employee of Oncoxx Biotech Srl. PS is an inventor in a patent application under consideration (EP3546948).

Author information

Author notes

  1. Pasquale Simeone

    Present address: Department of Medicine and Aging Sciences, University “G. D’Annunzio”, Chieti, Italy

  2. Pasquale Simeone

    Present address: Laboratory of Cytomorphology, Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio”, Chieti, Italy

  3. Andrea Sacchetti

    Present address: Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands

  4. Kristina Havas

    Present address: FIRC Institute of Molecular Oncology (IFOM), Milan, Italy

  5. These authors contributed equally: Marco Trerotola, Saverio Alberti.

Authors and Affiliations

  1. Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio”, Chieti, Italy

    Emanuela Guerra, Valeria Relli, Martina Ceci, Romina Tripaldi, Pasquale Simeone, Anna Laura Aloisi, Ludovica Pantalone, Rossana La Sorda, Rossano Lattanzio, Andrea Sacchetti, Kristina Havas, Mauro Piantelli, Marco Trerotola & Saverio Alberti

  2. Department of Medical, Oral and Biotechnological Sciences, University “G. D’Annunzio”, Chieti, Italy

    Emanuela Guerra, Nicola Tinari, Mauro Piantelli & Marco Trerotola

  3. Department of Innovative Technologies in Medicine & Dentistry, University “G.D’Annunzio”, Chieti, Italy

    Rossano Lattanzio

  4. Laboratory of Cell Physiology, Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio”, Chieti, Italy

    Simone Guarnieri

  5. Department of Neuroscience, Imaging and Clinical Sciences, University “G. D’Annunzio”, Chieti, Italy

    Simone Guarnieri

  6. Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy

    Daniele Vergara

  7. Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse, Université de Lille 1, Cité Scientifique, Villeneuve D’Ascq Cedex, France

    Isabelle Fournier & Michel Salzet

  8. Unit of Medical Genetics, Department of Biomedical Sciences, University of Messina, Messina, Italy

    Saverio Alberti

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Contributions

MT, VR, RT, AS, KH, PS, EG, MC, and and ALA performed the biochemical and functional assays; RLS, RL, NT, and MP collected the human tumor samples, assembled tissue microarrays, and performed IHC analysis; DV. performed the 2D-PAGE and the NanoLC-MS/MS assays; DV, IF, and MS analyzed the data from NanoLC and MS/MS assays; MT and SA planned the study and wrote the paper.

Corresponding authors

Correspondence to Marco Trerotola or Saverio Alberti.

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Competing interests

The authors declare no competing interests.

Ethics approval

All procedures involving animal care were approved by the Interuniversity Animal Research Ethics Committee (CEISA), Chieti-Pescara and Teramo Universities (Prot. 26/2011/CEISA/PROG/16), and were conducted in compliance with consensus international protocols (D.L. No. 116, G.U. Feb. 18,1992; No. 8, G.U. July, 1994; UKCCCR Guidelines for the Welfare of Animals in Experimental Neoplasia; EEC Council Directive 86/609, Dec. 12,1987; Guide for the Care and Use of Laboratory Animals, US-NRC,1996). Studies on human tumor samples were approved by the Italian Ministry of Health (RicOncol RF-EMR-2006-361866).

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Guerra, E., Relli, V., Ceci, M. et al. Trop-2, Na+/K+ ATPase, CD9, PKCα, cofilin assemble a membrane signaling super-complex that drives colorectal cancer growth and invasion. Oncogene 41, 1795–1808 (2022). https://doi.org/10.1038/s41388-022-02220-1

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