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


Roe J.-S.,Cold Spring Harbor Laboratory | Hwang C.-I.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Somerville T.D.D.,Cold Spring Harbor Laboratory | Milazzo J.P.,Cold Spring Harbor Laboratory | And 19 more authors.
Cell | Year: 2017

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis. Large-scale enhancer reprogramming directed by transcription factors such as FOXA1 drives metastasis in the organoid model of pancreatic cancer. © 2017 Elsevier Inc.


Feigin M.E.,Cold Spring Harbor Laboratory | Feigin M.E.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Garvin T.,Cold Spring Harbor Laboratory | Bailey P.,University of Glasgow | And 26 more authors.
Nature Genetics | Year: 2017

The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.


Feigin M.E.,Cold Spring Harbor Laboratory | Feigin M.E.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Tuveson D.A.,Cold Spring Harbor Laboratory | Tuveson D.A.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Tuveson D.A.,Sloan Kettering Cancer Center
Cold Spring Harbor Symposia on Quantitative Biology | Year: 2016

The ability to faithfully model complex processes lies at the heart of experimental biology. Although a reductionist approach necessarily reduces this complexity, it is nevertheless required for untangling the contributions and interactions of the various system components. It has long been appreciated that cancer is a complex process that involves positive and negative interactions between tumor cells, normal host tissue, and the associated cells of the tumor microenvironment. However, accurate models for studying these complex interactions in vitro have remained elusive.We seek to generate models of mouse and human pancreatic cancer that are relevant to disease biology and useful for elucidating poorly understood facets of this deadly disease. The ability to model, manipulate, and predict the therapeutic response of an individual's disease outside their body represents the promise of precision medicine. Therefore, these models are patient-specific and allow the identification of new biomarkers and novel treatment modalities for rapid translation to the clinic. In this perspective we will discuss recent advances in modeling pancreatic cancer in vitro, the discoveries these models have enabled, and future challenges and opportunities awaiting further investigation. © 2016 Feigin and Tuveson.


Chio I.I.C.,Cold Spring Harbor Laboratory | Chio I.I.C.,Lustgarten Foundation Pancreatic Cancer Research Laboratory | Tuveson D.A.,Cold Spring Harbor Laboratory | Tuveson D.A.,Lustgarten Foundation Pancreatic Cancer Research Laboratory
Trends in Molecular Medicine | Year: 2017

An unanswered question in human health is whether antioxidation prevents or promotes cancer. Antioxidation has historically been viewed as chemopreventive, but emerging evidence suggests that antioxidants may be supportive of neoplasia. We posit this contention to be rooted in the fact that ROS do not operate as one single biochemical entity, but as diverse secondary messengers in cancer cells. This cautions against therapeutic strategies to increase ROS at a global level. To leverage redox alterations towards the development of effective therapies necessitates the application of biophysical and biochemical approaches to define redox dynamics and to functionally elucidate specific oxidative modifications in cancer versus normal cells. An improved understanding of the sophisticated workings of redox biology is imperative to defeating cancer. © 2017 Elsevier Ltd


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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