p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis

Laura Solé, Teresa Lobo-Jarne, Daniel Álvarez-Villanueva, Josune Alonso-Marañón, Yolanda Guillén, Marta Guix, Irene Sangrador, Catalina Rozalén, Anna Vert, Antonio Barbachano, Joan Lop, Marta Salido, Beatriz Bellosillo, Raquel García-Romero, Marta Garrido, Jessica González, María Martínez-Iniesta, Erika López-Arribillaga, Ramón Salazar, Clara Montagut, Ferrán Torres, Mar Iglesias, Toni Celià-Terrassa, Alberto Muñoz, Alberto Villanueva, Anna Bigas () and Lluís Espinosa ()
Additional contact information
Laura Solé: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Teresa Lobo-Jarne: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Daniel Álvarez-Villanueva: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Josune Alonso-Marañón: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Yolanda Guillén: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Marta Guix: Universitat Pompeu Fabra
Irene Sangrador: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Catalina Rozalén: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Anna Vert: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Antonio Barbachano: CIBERONC, Instituto de Salud Carlos III
Joan Lop: Universitat Autònoma de Barcelona
Marta Salido: Universitat Autònoma de Barcelona
Beatriz Bellosillo: CIBERONC, Instituto de Salud Carlos III
Raquel García-Romero: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Marta Garrido: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Jessica González: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
María Martínez-Iniesta: L’Hospitalet del Llobregat
Erika López-Arribillaga: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Ramón Salazar: CIBERONC, Instituto de Salud Carlos III
Clara Montagut: CIBERONC, Instituto de Salud Carlos III
Ferrán Torres: Universitat Autònoma de Barcelona
Mar Iglesias: CIBERONC, Instituto de Salud Carlos III
Toni Celià-Terrassa: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Alberto Muñoz: CIBERONC, Instituto de Salud Carlos III
Alberto Villanueva: L’Hospitalet del Llobregat
Anna Bigas: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar
Lluís Espinosa: Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription.

Date: 2022
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DOI: 10.1038/s41467-022-30382-9

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