Lustgarten Foundation Pancreatic Cancer Research Laboratory

Cold Spring Harbor, NY, United States

Lustgarten Foundation Pancreatic Cancer Research Laboratory

Cold Spring Harbor, NY, United States

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Chio I.I.C.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Tuveson D.A.,Lustgarten Foundation Pancreatic Cancer Research Laboratory
Cell Cycle | Year: 2017

Pancreatic ductal adenocarcinoma (PDA) holds the most dismal prognosis among the common malignancies and is considered to be largely incurable. In spite of extensive efforts in preclinical and clinical science, the survival rate of pancreatic cancer has not improved substantially over the past 40 y. An activating mutation of KRAS is the most common genetic perturbation found in PDA, occurring in 90–95% of the cases. Despite the identification of a clear driver oncogene, clinically actionable strategies to target KRAS have not yet been identified. A deeper understanding of the molecular events downstream of KRAS is therefore critical for the development of new therapeutic interventions for this deadly disease. © 2017 Taylor & Francis


Chio I.I.C.,Cold Spring Harbor Laboratory | Chio I.I.C.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Jafarnejad S.M.,McGill University | Ponz-Sarvise M.,Cold Spring Harbor Laboratory | And 32 more authors.
Cell | Year: 2016

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease. © 2016 Elsevier Inc.


PubMed | McGill University, Montana State University, University of Michigan, Sloan Kettering Cancer Center and 4 more.
Type: Journal Article | Journal: Cell | Year: 2016

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulatorNfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary tomaintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer exvivo and invivo, representing a promising synthetic lethal strategy for treating the disease.


Hwang C.-I.,Cold Spring Harbor Laboratory | Hwang C.-I.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Boj S.F.,Netherlands Cancer Institute | Boj S.F.,Foundation Hubrecht Organoid Technology HUB | And 3 more authors.
Journal of Pathology | Year: 2016

Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. Despite intensive efforts, the translation of findings in preclinical studies has been ineffective, due partially to the lack of preclinical models that faithfully recapitulate features of human PDA. Here, we review current preclinical models for human PDA (eg human PDA cell lines, cell line-based xenografts and patient-derived tumour xenografts). In addition, we discuss potential applications of the recently developed pancreatic ductal organoids, three-dimensional culture systems and organoid-based xenografts as new preclinical models for PDA. © 2015 Pathological Society of Great Britain and Ireland.


Boj S.F.,University Utrecht | Boj S.F.,Foundation Hubrecht Organoid Technology HUB | Hwang C.-I.,Cold Spring Harbor Laboratory | Hwang C.-I.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | And 77 more authors.
Cell | Year: 2015

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy. © 2015 Elsevier Inc. All rights reserved.

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