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

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. © 2022. The Author(s).

Citation

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, Lluís Espinosa. p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis. Nature communications. 2022 May 23;13(1):2866

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PMID: 35606354

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