Richard Drexler1, Rebecca Fahy2, Mirco Küchler2, Kim C Wagner2, Tim Reese2, Mareike Ehmke3, Bernd Feyerabend4, Moritz Kleine5, Karl J Oldhafer2. 1. Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany. Electronic address: richard.drexler@semmelweis-hamburg.de. 2. Asklepios Campus Hamburg, Semmelweis University Budapest, Hamburg, Germany; Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany. 3. Department of Surgery, Division of HPB Surgery, Asklepios Hospital Barmbek, Hamburg, Germany. 4. MVZ Hanse Histologikum GmbH, Hamburg, Germany. 5. Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
Abstract
BACKGROUND: Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive. METHODS: A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival. CONCLUSION: Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.
BACKGROUND: Transcriptional enhanced associated domain (TEAD) transcription factors are nuclear effectors of several oncogenic signalling pathways including Hippo, WNT, TGF-ß and EGFR pathways that interact with various cancer genes. The subcellular localization of TEAD regulates the functional output of these pathways affecting tumour progression and patient outcome. However, the impact of the TEAD family on pancreatic ductal adenocarcinoma (PDAC) and its clinical progression remain elusive. METHODS: A cohort of 81 PDAC patients who had undergone surgery was established. Cytoplasmic and nuclear localization of TEAD1, TEAD2, TEAD3 and TEAD4 was evaluated with the immunoreactive score (IRS) by immunohistochemistry (IHC) using paraffin-embedded tissue. Results were correlated with clinicopathological data, disease-free and overall survival. RESULTS: Nuclear staining of all four TEADs was increased in pancreatic cancer tissue. Patients suffering from metastatic disease at time of surgery showed a strong nuclear staining of TEAD2 and TEAD3 (p < 0.05). Furthermore, a nuclear > cytoplasmic ratio of TEAD2 and TEAD3 was associated with a shorter overall survival and TEAD2 emerged as an independent prognostic factor for disease-free survival. CONCLUSION: Our study underlines the importance of TEAD transcription factors in PDAC as a nuclear localization was found to be associated with metastatic disease and an unfavourable prognosis after surgical resection.