title: Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment.
abstract: Hippo is a tumor-suppressor pathway that negatively regulates the oncoproteins TAZ and YAP. Moreover, Hippo affects the biology of a variety of non-neoplastic cells in the tumor microenvironment, even including immune cells. We herein assessed the predictive role of TAZ and YAP, assessed by immunohistochemistry, in 50 cervical cancer patients prevalently treated with neoadjuvant chemotherapy. Tumors were classified as positive or negative according to the percentage of tumor-expressing cells and cellular localization. TAZ/YAP were also evaluated in non-neoplastic cells, namely endothelial cells, non-lymphocytic stromal cells and tumor-infiltrating lymphocytes (TILs). TAZ expression in cancer cells (TAZ(pos)) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZ(TIL+) and YAP(TIL+)) seemed to be associated with increased pCRs (p = 0.083 and p = 0.018, respectively). When testing the predictive significance of the concomitant expression of TAZ in cancer cells and its absence in TILs (TAZ(pos)/TAZ(TIL-)), patients with TAZ(pos)/TAZ(TIL-) showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZ(pos)/TAZ(TIL-): OR 8.67, 95% CI: 2.31-32.52, p = 0.001). Sensitivity analysis carried out in the 41 patients treated with neoadjuvant chemotherapy yielded comparable results (TAZ(pos)/TAZ(TIL-): OR 11.0, 95% CI: 2.42-49.91, p = 0.002). Internal validation carried out with two different procedures confirmed the robustness of this model. Overall, we found evidence on the association between TAZ expression in cervical cancer cells and reduced pCR rate. Conversely, the expression of the Hippo transducers in TILs may predict increased treatment efficacy, possibly mirroring the activation of a non-canonical Hippo/MST pathway necessary for T-cells activation and survival.
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Buglioni
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Sergi
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Antoniani
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Carosi
authors.affiliation: Medical Oncology Unit, ASL Frosinone , Frosinone, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gamucci
authors.affiliation: Department of Surgery, Gynecologic Oncology Unit, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vincenzoni
authors.affiliation: Department of Surgery, Gynecologic Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy; HPV-UNIT, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Department of Surgery, Gynecologic Oncology Unit, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Vizza
authors.affiliation: HPV-UNIT, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Venuti
authors.affiliation: Department of Radiotherapy, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sanguineti
authors.affiliation: Department of Experimental and Clinical Medicine, Division of Gynecology and Obstetrics, University of Pisa , Pisa, Italy.
authors.forename: Angiolo
authors.initials: A
authors.lastname: Gadducci
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy; Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, and CeSi-MeT, "G. d'Annunzio" University , Chieti, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Natoli
authors.affiliation: Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy; Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Scientific Direction, "Regina Elena" National Cancer Institute , Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Rome, Italy; Scientific Direction, "Regina Elena" National Cancer Institute, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maugeri-Saccà
keywords: Cervical cancer; Hippo pathway; Hippo transducers; TAZ; pathological complete response; tumor microenvironment; YAP