Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment

Simonetta Buglioni, Patrizia Vici, Domenico Sergi, Laura Pizzuti, Luigi Di Lauro, Barbara Antoniani, Francesca Sperati, Irene Terrenato, Mariantonia Carosi, Teresa Gamucci, Cristina Vincenzoni, Luciano Mariani, Enrico Vizza, Aldo Venuti, Giuseppe Sanguineti, Angiolo Gadducci, Maddalena Barba, Clara Natoli, Ilio Vitale, Marcella Mottolese & 2 others Ruggero De Maria, Marcello Maugeri-Saccà

Research output: Contribution to journalArticle

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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 (TAZpos) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZTIL+ and YAPTIL+) 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 (TAZpos/TAZTIL-), patients with TAZpos/TAZTIL- showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZpos/TAZTIL-: 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 (TAZpos/TAZTIL-: 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.

Original languageEnglish
Article numbere1160187
JournalOncoImmunology
Volume5
Issue number6
DOIs
Publication statusPublished - Jun 2 2016

Fingerprint

Tumor Microenvironment
Transducers
Uterine Cervical Neoplasms
Tumor-Infiltrating Lymphocytes
Neoplasms
Drug Therapy
Oncogene Proteins
Stromal Cells
Cell Survival
Multivariate Analysis
Endothelial Cells
Immunohistochemistry
T-Lymphocytes

Keywords

  • Cervical cancer
  • Hippo pathway
  • Hippo transducers
  • pathological complete response
  • TAZ
  • tumor microenvironment; YAP

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

Cite this

Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment. / Buglioni, Simonetta; Vici, Patrizia; Sergi, Domenico; Pizzuti, Laura; Di Lauro, Luigi; Antoniani, Barbara; Sperati, Francesca; Terrenato, Irene; Carosi, Mariantonia; Gamucci, Teresa; Vincenzoni, Cristina; Mariani, Luciano; Vizza, Enrico; Venuti, Aldo; Sanguineti, Giuseppe; Gadducci, Angiolo; Barba, Maddalena; Natoli, Clara; Vitale, Ilio; Mottolese, Marcella; De Maria, Ruggero; Maugeri-Saccà, Marcello.

In: OncoImmunology, Vol. 5, No. 6, e1160187, 02.06.2016.

Research output: Contribution to journalArticle

Buglioni, Simonetta ; Vici, Patrizia ; Sergi, Domenico ; Pizzuti, Laura ; Di Lauro, Luigi ; Antoniani, Barbara ; Sperati, Francesca ; Terrenato, Irene ; Carosi, Mariantonia ; Gamucci, Teresa ; Vincenzoni, Cristina ; Mariani, Luciano ; Vizza, Enrico ; Venuti, Aldo ; Sanguineti, Giuseppe ; Gadducci, Angiolo ; Barba, Maddalena ; Natoli, Clara ; Vitale, Ilio ; Mottolese, Marcella ; De Maria, Ruggero ; Maugeri-Saccà, Marcello. / Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment. In: OncoImmunology. 2016 ; Vol. 5, No. 6.
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T1 - Analysis of the hippo transducers TAZ and YAP in cervical cancer and its microenvironment

AU - Buglioni, Simonetta

AU - Vici, Patrizia

AU - Sergi, Domenico

AU - Pizzuti, Laura

AU - Di Lauro, Luigi

AU - Antoniani, Barbara

AU - Sperati, Francesca

AU - Terrenato, Irene

AU - Carosi, Mariantonia

AU - Gamucci, Teresa

AU - Vincenzoni, Cristina

AU - Mariani, Luciano

AU - Vizza, Enrico

AU - Venuti, Aldo

AU - Sanguineti, Giuseppe

AU - Gadducci, Angiolo

AU - Barba, Maddalena

AU - Natoli, Clara

AU - Vitale, Ilio

AU - Mottolese, Marcella

AU - De Maria, Ruggero

AU - Maugeri-Saccà, Marcello

N1 - Vitale in doppia affiliazione IRE/Tor Vergata

PY - 2016/6/2

Y1 - 2016/6/2

N2 - 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 (TAZpos) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZTIL+ and YAPTIL+) 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 (TAZpos/TAZTIL-), patients with TAZpos/TAZTIL- showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZpos/TAZTIL-: 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 (TAZpos/TAZTIL-: 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.

AB - 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 (TAZpos) was associated with a reduced pathological complete response (pCR) rate (p = 0.041). Conversely, the expression of TAZ and YAP in TILs (TAZTIL+ and YAPTIL+) 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 (TAZpos/TAZTIL-), patients with TAZpos/TAZTIL- showed lower pCR rate (p = 0.001), as confirmed in multivariate analysis (TAZpos/TAZTIL-: 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 (TAZpos/TAZTIL-: 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.

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KW - TAZ

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