Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.

Hedgehog-GLI and notch pathways sustain chemoresistance and invasiveness in colorectal cancer and their Inhibition restores chemotherapy efficacy / Citarella, Anna; Catanzaro, Giuseppina; Besharat, ZEIN MERSINI; Trocchianesi, Sofia; Barbagallo, Federica; Gosti, Giorgio; Leonetti, Marco; DI FIORE, Annamaria; Coppola, Lucia; Autilio, TANJA MILENA; Spinello, Zaira; Vacca, Alessandra; DE SMAELE, Enrico; Venneri, MARY ANNA; Ferretti, Elisabetta; Masuelli, Laura; Po, Agnese. - In: CANCERS. - ISSN 2072-6694. - 15:5(2023), pp. 1-16. [10.3390/cancers15051471]

Hedgehog-GLI and notch pathways sustain chemoresistance and invasiveness in colorectal cancer and their Inhibition restores chemotherapy efficacy

Anna Citarella;Giuseppina Catanzaro;Zein Mersini Besharat;Sofia Trocchianesi;Federica Barbagallo;Giorgio Gosti;Marco Leonetti;Annamaria Di Fiore;Lucia Coppola;Tanja Milena Autilio;Zaira Spinello;Alessandra Vacca;Enrico De Smaele;Mary Anna Venneri;Elisabetta Ferretti;Laura Masuelli;Agnese Po
2023

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC.
2023
chemoresistance; colorectal cancer; epithelial-to-mesenchymal transition; organoids; signaling pathways
01 Pubblicazione su rivista::01a Articolo in rivista
Hedgehog-GLI and notch pathways sustain chemoresistance and invasiveness in colorectal cancer and their Inhibition restores chemotherapy efficacy / Citarella, Anna; Catanzaro, Giuseppina; Besharat, ZEIN MERSINI; Trocchianesi, Sofia; Barbagallo, Federica; Gosti, Giorgio; Leonetti, Marco; DI FIORE, Annamaria; Coppola, Lucia; Autilio, TANJA MILENA; Spinello, Zaira; Vacca, Alessandra; DE SMAELE, Enrico; Venneri, MARY ANNA; Ferretti, Elisabetta; Masuelli, Laura; Po, Agnese. - In: CANCERS. - ISSN 2072-6694. - 15:5(2023), pp. 1-16. [10.3390/cancers15051471]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1677425
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