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Papers by Stuart Fine

Research paper thumbnail of Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1

Oncogene, 2021

Authors' contribution HY and CY were responsible for the designs of the experiments, the acquisit... more Authors' contribution HY and CY were responsible for the designs of the experiments, the acquisition, analyses, interpretation, and presentation of the data, and drafting the manuscript. SAF, ALY, YY, JY, DCK, ECC, EIC, and WQ contributed to the acquisition and analyses of the data. RAF, HY (Ying), and EIC were responsible for the computational analyses, statistical analyses, and interpretation of the data. EIC, JL, YM, and GHS provided resources and materials that were vital to the completion of the work. HY, CY, SAF, RAF, EIC, JL, WQ, and GHS prepared and revised the manuscript. WQ and GHS conceived and designed the work that led to the submission. Each author has made substantial contributions to the work and/or have been involved in drafting or revising the manuscript. All the authors have given final approval of the version to be published and take public responsibility for appropriate portions of the content.

Research paper thumbnail of Abstract 1215: Loss of PTEN expression predicts poor prognosis in patients with intraductal papillary mucinous neoplasms of the pancreas

Cancer Research, 2013

Purpose: Previously we have reported PIK3CA gene mutations in high-grade intraductal papillary mu... more Purpose: Previously we have reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMNs). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) deregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. Here we conducted a comprehensive examination of the PI3K signaling pathway to gain an understanding of the extent of its deregulation in IPMN and the potential impact on clinical outcomes. Experimental Design: Thirty-six IPMN specimens were evaluated for the E542K and E545K (exon 9), and H1047R (exon 20) hot-spot mutations in the PIK3CA gene and E17K mutation in the AKT1 gene using novel mutant-enriched sequencing methods. PIK3CA and AKT1 gene amplifications and PTEN loss of heterozygosity (LOH) were also investigated. In addition, the expression levels of 3-phosphoinositide dependent protein kinase-1 (PDPK1/PDK1), PTEN/MMAC phosphatase and Ki67 proliferation marker were analyzed by immunoh...

Research paper thumbnail of Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis

Research paper thumbnail of AB002. S002. Wild-type KRAS allele exerts its tumor-suppressive function through decreased Yap1 activation in pancreatic cancer

Annals of Pancreatic Cancer, 2018

Research paper thumbnail of Loss of PTEN Expression Is Associated with Poor Prognosis in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas

Clinical Cancer Research, 2013

Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucino... more Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication. Experimental Design: Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry. Results: Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN versus low-grade ...

Research paper thumbnail of Abstract I17: Genomic loss of the wild-type KRAS allele in pancreatic tumor progression and metastasis

Cancer Research, 2019

KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). Intriguingly, human ... more KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). Intriguingly, human tumors with RAS mutations often display loss of the remaining wild-type (WT) allele, including PDAC. We previously reported that selective loss of WT Kras allele is associated with PDAC progression to metastasis in both mice and humans. These data suggest that WT KRAS functions as a tumor suppressor in the context of mutant KRAS and loss of WT KRAS offers growth advantage in clonal evolution and tumor progression to metastasis. To investigate the underlying mechanism, we have examined the impact of inducible WT KRAS expression on human PDAC cell lines that had spontaneously lost the WT allele. We observed re-expression of WT KRAS significantly attenuated the malignancy of pancreatic cancer cells in vitro and in vivo. RNA-Seq and proteomic analyses identified HIPPO signaling, specifically YAP1 activation, is inhibited by WT KRAS restoration. We observed a marked reduction of YAP1 nuclear ...

Research paper thumbnail of Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1

Oncogene, 2021

Authors' contribution HY and CY were responsible for the designs of the experiments, the acquisit... more Authors' contribution HY and CY were responsible for the designs of the experiments, the acquisition, analyses, interpretation, and presentation of the data, and drafting the manuscript. SAF, ALY, YY, JY, DCK, ECC, EIC, and WQ contributed to the acquisition and analyses of the data. RAF, HY (Ying), and EIC were responsible for the computational analyses, statistical analyses, and interpretation of the data. EIC, JL, YM, and GHS provided resources and materials that were vital to the completion of the work. HY, CY, SAF, RAF, EIC, JL, WQ, and GHS prepared and revised the manuscript. WQ and GHS conceived and designed the work that led to the submission. Each author has made substantial contributions to the work and/or have been involved in drafting or revising the manuscript. All the authors have given final approval of the version to be published and take public responsibility for appropriate portions of the content.

Research paper thumbnail of Abstract 1215: Loss of PTEN expression predicts poor prognosis in patients with intraductal papillary mucinous neoplasms of the pancreas

Cancer Research, 2013

Purpose: Previously we have reported PIK3CA gene mutations in high-grade intraductal papillary mu... more Purpose: Previously we have reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMNs). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) deregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. Here we conducted a comprehensive examination of the PI3K signaling pathway to gain an understanding of the extent of its deregulation in IPMN and the potential impact on clinical outcomes. Experimental Design: Thirty-six IPMN specimens were evaluated for the E542K and E545K (exon 9), and H1047R (exon 20) hot-spot mutations in the PIK3CA gene and E17K mutation in the AKT1 gene using novel mutant-enriched sequencing methods. PIK3CA and AKT1 gene amplifications and PTEN loss of heterozygosity (LOH) were also investigated. In addition, the expression levels of 3-phosphoinositide dependent protein kinase-1 (PDPK1/PDK1), PTEN/MMAC phosphatase and Ki67 proliferation marker were analyzed by immunoh...

Research paper thumbnail of Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis

Research paper thumbnail of AB002. S002. Wild-type KRAS allele exerts its tumor-suppressive function through decreased Yap1 activation in pancreatic cancer

Annals of Pancreatic Cancer, 2018

Research paper thumbnail of Loss of PTEN Expression Is Associated with Poor Prognosis in Patients with Intraductal Papillary Mucinous Neoplasms of the Pancreas

Clinical Cancer Research, 2013

Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucino... more Purpose: Previously, we reported PIK3CA gene mutations in high-grade intraductal papillary mucinous neoplasms (IPMN). However, the contribution of phosphatidylinositol-3 kinase pathway (PI3K) dysregulation to pancreatic carcinogenesis is not fully understood and its prognostic value unknown. We investigated the dysregulation of the PI3K signaling pathway in IPMN and its clinical implication. Experimental Design: Thirty-six IPMN specimens were examined by novel mutant-enriched sequencing methods for hot-spot mutations in the PIK3CA and AKT1 genes. PIK3CA and AKT1 gene amplifications and loss of heterozygosity at the PTEN locus were also evaluated. In addition, the expression levels of PDPK1/PDK1, PTEN, and Ki67 were analyzed by immunohistochemistry. Results: Three cases carrying the E17K mutation in the AKT1 gene and one case harboring the H1047R mutation in the PIK3CA gene were detected among the 36 cases. PDK1 was significantly overexpressed in the high-grade IPMN versus low-grade ...

Research paper thumbnail of Abstract I17: Genomic loss of the wild-type KRAS allele in pancreatic tumor progression and metastasis

Cancer Research, 2019

KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). Intriguingly, human ... more KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). Intriguingly, human tumors with RAS mutations often display loss of the remaining wild-type (WT) allele, including PDAC. We previously reported that selective loss of WT Kras allele is associated with PDAC progression to metastasis in both mice and humans. These data suggest that WT KRAS functions as a tumor suppressor in the context of mutant KRAS and loss of WT KRAS offers growth advantage in clonal evolution and tumor progression to metastasis. To investigate the underlying mechanism, we have examined the impact of inducible WT KRAS expression on human PDAC cell lines that had spontaneously lost the WT allele. We observed re-expression of WT KRAS significantly attenuated the malignancy of pancreatic cancer cells in vitro and in vivo. RNA-Seq and proteomic analyses identified HIPPO signaling, specifically YAP1 activation, is inhibited by WT KRAS restoration. We observed a marked reduction of YAP1 nuclear ...