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

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 Ca 2+ signal. We reveal here that Trop-2 binds the cell membrane Na + /K + -ATPase, and that clustering of Trop-2 induces an intracellular Ca 2+ 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. CRISPRbased 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.

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

“…The knockdown of TROP2 showed the opposite effect and inhibited metastasis [ 28 ]. Recently, it was found that TROP2 binds to CD9 and is subsequently phosphorylated by PKCα, leading to the activation of AKT and ERK, which in turn causes β-actin cytoskeleton remodeling and tumor progression [ 29 ].…”

ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2

“…Additionally, we have revealed a potentially more decisive function of TROP2 in de-adhesion of cancer cells as the starting point of metastasis. TROP2 was localized in long cell protrusions interspersing ATF2-negative cell aggregates, linking its function to the cytoskeleton machinery as recently described [ 33 ]. Such filopodia act as sensors for signals, such as chemo-attractants or nutrients.…”

AIOM Abstract

“…1 , Chella A. 5 , Amoroso D. 1 , Baldini E. 4 1 Medical Oncology, Versilia Hospital, Azienda USL Toscana Nord-Ovest, Lido di Camaiore; 2 SODc Oncologia Medica -Azienda Ospedaliero Universitaria Careggi, Firenze; 3 Radiation Oncology Unit, Oncology Department, AOU Careggi, Firenze; 4 Medical Oncology, San Luca Hospital, Azienda USL Toscana Nord-Ovest, Lucca; 5 Unit of Pneumo-Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa; 6 Medical Oncology, Azienda Ospedaliera Universitaria Senese, Siena Background: Limited evidence is available concerning the efficacy and safety of chemotherapy after previous immunotherapy in advanced NSCLC patients.…”

“…2 , Montanino A. 2 , Sandomenico C. 2 , Sforza V. 2 , Costanzo R. 2 , Damiano S. 2 , La Manna C. 2 , Martucci N. 2 , La Rocca A. 2 , De Luca G. 2 , Totaro G. 2 , De Cecio R. 2 , Picone C. 2 , D'Auria S. 2 , Normanno N. 2 , Pascarella G. 2 1 Istituto Nazionale Tumori, Fondazione G. Pascale,Napoli;2 Istituto Nazionale Tumori Pascale, Napoli Background: Objective of the present study was to highlight the sources of harm that could negatively impact on decision making or affect the planning process of a Lung Multidisciplinary Team (MDT), in order to define the level of risk of each factor, evaluating the likelihood and severity of harm and suggesting risk mitigation measures.…”