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216 results on '"Tiriac, Hervé"'

1. Inhibiting stromal Class I HDACs curbs pancreatic cancer progression.

Author

Liang, Gaoyang, Oh, Tae, Hah, Nasun, Tiriac, Hervé, Shi, Yu, Truitt, Morgan, Antal, Corina, Atkins, Annette, Li, Yuwenbin, Fraser, Cory, Ng, Serina, Pinto, Antonio, Nelson, Dylan, Estepa, Gabriela, Bashi, Senada, Banayo, Ester, Dai, Yang, Liddle, Christopher, Yu, Ruth, Hunter, Tony, Engle, Dannielle, Han, Haiyong, Von Hoff, Daniel, Downes, Michael, and Evans, Ronald

Subjects
Animals, Mice, Cell Line, Tumor, Pancreatic Neoplasms, Pancreas, Carcinoma, Pancreatic Ductal, Fibroblasts, Carcinogenesis, Tumor Microenvironment
Abstract

Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

Published
2023

2. Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma

Author

Gulay, Kevin Christian Montecillo, Zhang, Xinlian, Pantazopoulou, Vasiliki, Patel, Jay, Esparza, Edgar, Babu, Deepa Sheik Pran, Ogawa, Satoshi, Weitz, Jonathan, Ng, Isabella, Mose, Evangeline S, Pu, Minya, Engle, Dannielle D, Lowy, Andrew M, and Tiriac, Hervé

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Orphan Drug, Pancreatic Cancer, Rare Diseases, Digestive Diseases, 5.1 Pharmaceuticals, Mice, Animals, Afatinib, ErbB Receptors, Proto-Oncogene Proteins p21(ras), Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Mutation, Cell Line, Tumor, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.SignificanceKRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.

Published
2023

3. A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer

Author

Antal, Corina E, Oh, Tae Gyu, Aigner, Stefan, Luo, En-Ching, Yee, Brian A, Campos, Tania, Tiriac, Hervé, Rothamel, Katherine L, Cheng, Zhang, Jiao, Henry, Wang, Allen, Hah, Nasun, Lenkiewicz, Elizabeth, Lumibao, Jan C, Truitt, Morgan L, Estepa, Gabriela, Banayo, Ester, Bashi, Senada, Esparza, Edgar, Munoz, Ruben M, Diedrich, Jolene K, Sodir, Nicole M, Mueller, Jasmine R, Fraser, Cory R, Borazanci, Erkut, Propper, David, Von Hoff, Daniel D, Liddle, Christopher, Yu, Ruth T, Atkins, Annette R, Han, Haiyong, Lowy, Andrew M, Barrett, Michael T, Engle, Dannielle D, Evan, Gerard I, Yeo, Gene W, Downes, Michael, and Evans, Ronald M

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Cancer, Digestive Diseases, Orphan Drug, Rare Diseases, Pancreatic Cancer, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Inflammatory and immune system, Male, Animals, Mice, RNA, Epigenesis, Genetic, Regulatory Sequences, Nucleic Acid, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Methyltransferases, RNA-Binding Proteins
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

Published
2023

4. Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

Miyabayashi, Koji, Baker, Lindsey A, Deschênes, Astrid, Traub, Benno, Caligiuri, Giuseppina, Plenker, Dennis, Alagesan, Brinda, Belleau, Pascal, Li, Siran, Kendall, Jude, Jang, Gun Ho, Kawaguchi, Risa Karakida, Somerville, Tim DD, Tiriac, Hervé, Hwang, Chang-Il, Burkhart, Richard A, Roberts, Nicholas J, Wood, Laura D, Hruban, Ralph H, Gillis, Jesse, Krasnitz, Alexander, Vakoc, Christopher R, Wigler, Michael, Notta, Faiyaz, Gallinger, Steven, Park, Youngkyu, and Tuveson, David A

Subjects
Rare Diseases, Clinical Research, Cancer, Pancreatic Cancer, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Mice, Pancreatic Ducts, Prognosis, Oncology and Carcinogenesis
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.See related commentary by Pickering and Morton, p. 1448.This article is highlighted in the In This Issue feature, p. 1426.

Published
2020

5. Improving natural product research translation: From source to clinical trial

Author

Sorkin, Barbara C, Kuszak, Adam J, Bloss, Gregory, Fukagawa, Naomi K, Hoffman, Freddie Ann, Jafari, Mahtab, Barrett, Bruce, Brown, Paula N, Bushman, Frederic D, Casper, Steven J, Chilton, Floyd H, Coffey, Christopher S, Ferruzzi, Mario G, Hopp, D Craig, Kiely, Mairead, Lakens, Daniel, MacMillan, John B, Meltzer, David O, Pahor, Marco, Paul, Jeffrey, Pritchett‐Corning, Kathleen, Quinney, Sara K, Rehermann, Barbara, Setchell, Kenneth DR, Sipes, Nisha S, Stephens, Jacqueline M, Taylor, D Lansing, Tiriac, Hervé, Walters, Michael A, Xi, Dan, Zappalá, Giovanna, and Pauli, Guido F

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Complementary and Integrative Health, Good Health and Well Being, Animals, Biological Products, Drug Evaluation, Preclinical, Ethnobotany, Humans, Translational Research, Biomedical, clinical predictive validity, dietary supplements, model systems, rigor and replicability, value of information, Biochemistry and Cell Biology, Physiology, Medical Physiology, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical physiology
Abstract

While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

Published
2020

6. Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer

Author

Ponz-Sarvise, Mariano, Corbo, Vincenzo, Tiriac, Hervé, Engle, Dannielle D, Frese, Kristopher K, Oni, Tobiloba E, Hwang, Chang-Il, Öhlund, Daniel, Chio, Iok In Christine, Baker, Lindsey A, Filippini, Dea, Wright, Kevin, Bapiro, Tashinga E, Huang, Pearl, Smith, Paul, Yu, Kenneth H, Jodrell, Duncan I, Park, Youngkyu, and Tuveson, David A

Subjects
Cancer, Pancreatic Cancer, Rare Diseases, Digestive Diseases, Clinical Research, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Antineoplastic Agents, Cell Line, Tumor, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Humans, Mice, Mice, Transgenic, Organoids, Pancreatic Neoplasms, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Signal Transduction, Tissue Culture Techniques, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PURPOSE:KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. EXPERIMENTAL DESIGN:We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. In addition, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities. RESULTS:Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. CONCLUSIONS:Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models, pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT, and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.

Published
2019

7. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice

Author

Engle, Dannielle D, Tiriac, Hervé, Rivera, Keith D, Pommier, Arnaud, Whalen, Sean, Oni, Tobiloba E, Alagesan, Brinda, Lee, Eun Jung, Yao, Melissa A, Lucito, Matthew S, Spielman, Benjamin, Da Silva, Brandon, Schoepfer, Christina, Wright, Kevin, Creighton, Brianna, Afinowicz, Lauren, Yu, Kenneth H, Grützmann, Robert, Aust, Daniela, Gimotty, Phyllis A, Pollard, Katherine S, Hruban, Ralph H, Goggins, Michael G, Pilarsky, Christian, Park, Youngkyu, Pappin, Darryl J, Hollingsworth, Michael A, and Tuveson, David A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Cancer, Rare Diseases, Pancreatic Cancer, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Acute Disease, Animals, CA-19-9 Antigen, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Chronic Disease, ErbB Receptors, Extracellular Matrix Proteins, Fucosyltransferases, Galactosyltransferases, Glycosylation, Humans, Mice, Molecular Targeted Therapy, Pancreatic Neoplasms, Pancreatitis, General Science & Technology
Abstract

Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.

Published
2019

9. Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Author

Tiriac, Hervé, Belleau, Pascal, Engle, Dannielle D, Plenker, Dennis, Deschênes, Astrid, Somerville, Tim DD, Froeling, Fieke EM, Burkhart, Richard A, Denroche, Robert E, Jang, Gun-Ho, Miyabayashi, Koji, Young, C Megan, Patel, Hardik, Ma, Michelle, LaComb, Joseph F, Palmaira, Randze Lerie D, Javed, Ammar A, Huynh, Jasmine C, Johnson, Molly, Arora, Kanika, Robine, Nicolas, Shah, Minita, Sanghvi, Rashesh, Goetz, Austin B, Lowder, Cinthya Y, Martello, Laura, Driehuis, Else, LeComte, Nicolas, Askan, Gokce, Iacobuzio-Donahue, Christine A, Clevers, Hans, Wood, Laura D, Hruban, Ralph H, Thompson, Elizabeth, Aguirre, Andrew J, Wolpin, Brian M, Sasson, Aaron, Kim, Joseph, Wu, Maoxin, Bucobo, Juan Carlos, Allen, Peter, Sejpal, Divyesh V, Nealon, William, Sullivan, James D, Winter, Jordan M, Gimotty, Phyllis A, Grem, Jean L, DiMaio, Dominick J, Buscaglia, Jonathan M, Grandgenett, Paul M, Brody, Jonathan R, Hollingsworth, Michael A, O'Kane, Grainne M, Notta, Faiyaz, Kim, Edward, Crawford, James M, Devoe, Craig, Ocean, Allyson, Wolfgang, Christopher L, Yu, Kenneth H, Li, Ellen, Vakoc, Christopher R, Hubert, Benjamin, Fischer, Sandra E, Wilson, Julie M, Moffitt, Richard, Knox, Jennifer, Krasnitz, Alexander, Gallinger, Steven, and Tuveson, David A

Subjects
Organoids, Tumor Cells, Cultured, Humans, Pancreatic Neoplasms, Antineoplastic Agents, Drug Screening Assays, Antitumor, Prospective Studies, Gene Expression Profiling, Sequence Analysis, RNA, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Gene Regulatory Networks, Molecular Targeted Therapy, Standard of Care, Precision Medicine, Genetics, Pancreatic Cancer, Rare Diseases, Digestive Diseases, Orphan Drug, Cancer, Detection, screening and diagnosis, Development of treatments and therapeutic interventions, 4.1 Discovery and preclinical testing of markers and technologies, 5.1 Pharmaceuticals, Good Health and Well Being, Oncology and Carcinogenesis
Abstract

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112-29. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

Published
2018

10. Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Author

Roe, Jae-Seok, Hwang, Chang-Il, Somerville, Tim DD, Milazzo, Joseph P, Lee, Eun Jung, Da Silva, Brandon, Maiorino, Laura, Tiriac, Hervé, Young, C Megan, Miyabayashi, Koji, Filippini, Dea, Creighton, Brianna, Burkhart, Richard A, Buscaglia, Jonathan M, Kim, Edward J, Grem, Jean L, Lazenby, Audrey J, Grunkemeyer, James A, Hollingsworth, Michael A, Grandgenett, Paul M, Egeblad, Mikala, Park, Youngkyu, Tuveson, David A, and Vakoc, Christopher R

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cancer, Rare Diseases, Pancreatic Cancer, Digestive Diseases, Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Disease Models, Animal, Enhancer Elements, Genetic, Epigenomics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hepatocyte Nuclear Factor 3-alpha, Humans, Male, Mice, Mice, Inbred C57BL, Neoplasm Metastasis, Organoids, Pancreas, Pancreatic Neoplasms, FOXA1, enhancer, metastasis, organoid, pancreatic cancer, pancreatic ductal adenocarcinoma, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

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.

Published
2017

11. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Author

Öhlund, Daniel, Handly-Santana, Abram, Biffi, Giulia, Elyada, Ela, Almeida, Ana S, Ponz-Sarvise, Mariano, Corbo, Vincenzo, Oni, Tobiloba E, Hearn, Stephen A, Lee, Eun Jung, Chio, Iok In Christine, Hwang, Chang-Il, Tiriac, Hervé, Baker, Lindsey A, Engle, Dannielle D, Feig, Christine, Kultti, Anne, Egeblad, Mikala, Fearon, Douglas T, Crawford, James M, Clevers, Hans, Park, Youngkyu, and Tuveson, David A

Subjects
Rare Diseases, Pancreatic Cancer, Cancer, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Actins, Animals, Carcinoma, Pancreatic Ductal, Cells, Cultured, Cytokines, Fibroblasts, Humans, Mice, Mice, Inbred C57BL, Myofibroblasts, Pancreatic Neoplasms, STAT3 Transcription Factor, Medical and Health Sciences, Immunology
Abstract

Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

Published
2017

15. Organoid models of human and mouse ductal pancreatic cancer.

Author

Boj, Sylvia F, Hwang, Chang-Il, Baker, Lindsey A, Chio, Iok In Christine, Engle, Dannielle D, Corbo, Vincenzo, Jager, Myrthe, Ponz-Sarvise, Mariano, Tiriac, Hervé, Spector, Mona S, Gracanin, Ana, Oni, Tobiloba, Yu, Kenneth H, van Boxtel, Ruben, Huch, Meritxell, Rivera, Keith D, Wilson, John P, Feigin, Michael E, Öhlund, Daniel, Handly-Santana, Abram, Ardito-Abraham, Christine M, Ludwig, Michael, Elyada, Ela, Alagesan, Brinda, Biffi, Giulia, Yordanov, Georgi N, Delcuze, Bethany, Creighton, Brianna, Wright, Kevin, Park, Youngkyu, Morsink, Folkert HM, Molenaar, I Quintus, Borel Rinkes, Inne H, Cuppen, Edwin, Hao, Yuan, Jin, Ying, Nijman, Isaac J, Iacobuzio-Donahue, Christine, Leach, Steven D, Pappin, Darryl J, Hammell, Molly, Klimstra, David S, Basturk, Olca, Hruban, Ralph H, Offerhaus, George Johan, Vries, Robert GJ, Clevers, Hans, and Tuveson, David A

Subjects
Pancreas, Organoids, Animals, Mice, Inbred C57BL, Humans, Mice, Mice, Nude, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Organ Culture Techniques, Models, Biological, Cancer, Pancreatic Cancer, Rare Diseases, Biotechnology, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

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.

Published
2015

19. Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma

Author

Recouvreux, Maria Victoria, primary, Grenier, Shea F., additional, Zhang, Yijuan, additional, Esparza, Edgar, additional, Lambies, Guillem, additional, Galapate, Cheska Marie, additional, Maganti, Swetha, additional, Duong-Polk, Karen, additional, Bhullar, Deepika, additional, Naeem, Razia, additional, Scott, David A., additional, Lowy, Andrew M., additional, Tiriac, Hervé, additional, and Commisso, Cosimo, additional

Published
2023
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20. Data from Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma

Author

Gulay, Kevin Christian Montecillo, primary, Zhang, Xinlian, primary, Pantazopoulou, Vasiliki, primary, Patel, Jay, primary, Esparza, Edgar, primary, Pran Babu, Deepa Sheik, primary, Ogawa, Satoshi, primary, Weitz, Jonathan, primary, Ng, Isabella, primary, Mose, Evangeline S., primary, Pu, Minya, primary, Engle, Dannielle D., primary, Lowy, Andrew M., primary, and Tiriac, Hervé, primary

Published
2023
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21. Table S1 from Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma

Author

Gulay, Kevin Christian Montecillo, primary, Zhang, Xinlian, primary, Pantazopoulou, Vasiliki, primary, Patel, Jay, primary, Esparza, Edgar, primary, Pran Babu, Deepa Sheik, primary, Ogawa, Satoshi, primary, Weitz, Jonathan, primary, Ng, Isabella, primary, Mose, Evangeline S., primary, Pu, Minya, primary, Engle, Dannielle D., primary, Lowy, Andrew M., primary, and Tiriac, Hervé, primary

Published
2023
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22. Supplemental Figures from Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma

Author

Gulay, Kevin Christian Montecillo, primary, Zhang, Xinlian, primary, Pantazopoulou, Vasiliki, primary, Patel, Jay, primary, Esparza, Edgar, primary, Pran Babu, Deepa Sheik, primary, Ogawa, Satoshi, primary, Weitz, Jonathan, primary, Ng, Isabella, primary, Mose, Evangeline S., primary, Pu, Minya, primary, Engle, Dannielle D., primary, Lowy, Andrew M., primary, and Tiriac, Hervé, primary

Published
2023
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23. Supplementary Data from Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma

Author

Gulay, Kevin Christian Montecillo, primary, Zhang, Xinlian, primary, Pantazopoulou, Vasiliki, primary, Patel, Jay, primary, Esparza, Edgar, primary, Pran Babu, Deepa Sheik, primary, Ogawa, Satoshi, primary, Weitz, Jonathan, primary, Ng, Isabella, primary, Mose, Evangeline S., primary, Pu, Minya, primary, Engle, Dannielle D., primary, Lowy, Andrew M., primary, and Tiriac, Hervé, primary

Published
2023
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24. Inhibiting Stromal Class I HDACs Curbs Pancreatic Cancer Progression

Author

Liang, Gaoyang, primary, Oh, Tae Gyu, additional, Hah, Nasun, additional, Tiriac, Hervé, additional, Shi, Yu, additional, Truitt, Morgan L., additional, Antal, Corina E., additional, Atkins, Annette R., additional, Li, Yuwenbin, additional, Fraser, Cory, additional, Ng, Serina, additional, Pinto, Antonio F. M., additional, Nelson, Dylan C., additional, Estepa, Gabriela, additional, Bashi, Senada, additional, Banayo, Ester, additional, Dai, Yang, additional, Liddle, Christopher, additional, Yu, Ruth T., additional, Hunter, Tony, additional, Engle, Dannielle D., additional, Han, Haiyong, additional, Von Hoff, Daniel D., additional, Downes, Michael, additional, and Evans, Ronald M., additional

Published
2023
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25. NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Author

Chio, Iok In Christine, Jafarnejad, Seyed Mehdi, Ponz-Sarvise, Mariano, Park, Youngkyu, Rivera, Keith, Palm, Wilhelm, Wilson, John, Sangar, Vineet, Hao, Yuan, Öhlund, Daniel, Wright, Kevin, Filippini, Dea, Lee, Eun Jung, Da Silva, Brandon, Schoepfer, Christina, Wilkinson, John Erby, Buscaglia, Jonathan M., DeNicola, Gina M., Tiriac, Herve, Hammell, Molly, Crawford, Howard C., Schmidt, Edward E., Thompson, Craig B., Pappin, Darryl J., Sonenberg, Nahum, and Tuveson, David A.

Published
2016
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28. A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.

Author

Luo, En-Ching, Luo, En-Ching, Yee, Brian, Campos, Tania, Tiriac, Hervé, Rothamel, Katherine, Cheng, Zhang, Jiao, Henry, Wang, Allen, Hah, Nasun, Lenkiewicz, Elizabeth, Lumibao, Jan, Truitt, Morgan, Estepa, Gabriela, Banayo, Ester, Bashi, Senada, Esparza, Edgar, Munoz, Ruben, Diedrich, Jolene, Sodir, Nicole, Mueller, Jasmine, Fraser, Cory, Borazanci, Erkut, Propper, David, Von Hoff, Daniel, Liddle, Christopher, Yu, Ruth, Atkins, Annette, Han, Haiyong, Lowy, Andrew, Barrett, Michael, Engle, Dannielle, Evan, Gerard, Yeo, Gene, Downes, Michael, Evans, Ronald, Antal, Corina, Oh, Tae, Aigner, Stefan, Luo, En-Ching, Luo, En-Ching, Yee, Brian, Campos, Tania, Tiriac, Hervé, Rothamel, Katherine, Cheng, Zhang, Jiao, Henry, Wang, Allen, Hah, Nasun, Lenkiewicz, Elizabeth, Lumibao, Jan, Truitt, Morgan, Estepa, Gabriela, Banayo, Ester, Bashi, Senada, Esparza, Edgar, Munoz, Ruben, Diedrich, Jolene, Sodir, Nicole, Mueller, Jasmine, Fraser, Cory, Borazanci, Erkut, Propper, David, Von Hoff, Daniel, Liddle, Christopher, Yu, Ruth, Atkins, Annette, Han, Haiyong, Lowy, Andrew, Barrett, Michael, Engle, Dannielle, Evan, Gerard, Yeo, Gene, Downes, Michael, Evans, Ronald, Antal, Corina, Oh, Tae, and Aigner, Stefan

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.

Published
2023

29. Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma.

Author

Gulay, Kevin, Gulay, Kevin, Zhang, Xinlian, Pantazopoulou, Vasiliki, Patel, Jay, Esparza, Edgar, Pran Babu, Deepa, Ogawa, Satoshi, Weitz, Jonathan, Ng, Isabella, Mose, Evangeline, Lowy, Andrew, Tiriac, Hervé, Pu, Minya, Engle, Dannielle, Gulay, Kevin, Gulay, Kevin, Zhang, Xinlian, Pantazopoulou, Vasiliki, Patel, Jay, Esparza, Edgar, Pran Babu, Deepa, Ogawa, Satoshi, Weitz, Jonathan, Ng, Isabella, Mose, Evangeline, Lowy, Andrew, Tiriac, Hervé, Pu, Minya, and Engle, Dannielle

Abstract

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer. SIGNIFICANCE: KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.

Published
2023

30. Supplementary Figure S7 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

Miyabayashi, Koji, primary, Baker, Lindsey A., primary, Deschênes, Astrid, primary, Traub, Benno, primary, Caligiuri, Giuseppina, primary, Plenker, Dennis, primary, Alagesan, Brinda, primary, Belleau, Pascal, primary, Li, Siran, primary, Kendall, Jude, primary, Jang, Gun Ho, primary, Kawaguchi, Risa Karakida, primary, Somerville, Tim D.D., primary, Tiriac, Hervé, primary, Hwang, Chang-Il, primary, Burkhart, Richard A., primary, Roberts, Nicholas J., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Gillis, Jesse, primary, Krasnitz, Alexander, primary, Vakoc, Christopher R., primary, Wigler, Michael, primary, Notta, Faiyaz, primary, Gallinger, Steven, primary, Park, Youngkyu, primary, and Tuveson, David A., primary

Published
2023
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31. Data from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

Miyabayashi, Koji, primary, Baker, Lindsey A., primary, Deschênes, Astrid, primary, Traub, Benno, primary, Caligiuri, Giuseppina, primary, Plenker, Dennis, primary, Alagesan, Brinda, primary, Belleau, Pascal, primary, Li, Siran, primary, Kendall, Jude, primary, Jang, Gun Ho, primary, Kawaguchi, Risa Karakida, primary, Somerville, Tim D.D., primary, Tiriac, Hervé, primary, Hwang, Chang-Il, primary, Burkhart, Richard A., primary, Roberts, Nicholas J., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Gillis, Jesse, primary, Krasnitz, Alexander, primary, Vakoc, Christopher R., primary, Wigler, Michael, primary, Notta, Faiyaz, primary, Gallinger, Steven, primary, Park, Youngkyu, primary, and Tuveson, David A., primary

Published
2023
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32. Supplementary Video3 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

Miyabayashi, Koji, primary, Baker, Lindsey A., primary, Deschênes, Astrid, primary, Traub, Benno, primary, Caligiuri, Giuseppina, primary, Plenker, Dennis, primary, Alagesan, Brinda, primary, Belleau, Pascal, primary, Li, Siran, primary, Kendall, Jude, primary, Jang, Gun Ho, primary, Kawaguchi, Risa Karakida, primary, Somerville, Tim D.D., primary, Tiriac, Hervé, primary, Hwang, Chang-Il, primary, Burkhart, Richard A., primary, Roberts, Nicholas J., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Gillis, Jesse, primary, Krasnitz, Alexander, primary, Vakoc, Christopher R., primary, Wigler, Michael, primary, Notta, Faiyaz, primary, Gallinger, Steven, primary, Park, Youngkyu, primary, and Tuveson, David A., primary

Published
2023
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33. Table S3 from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

Tiriac, Hervé, primary, Belleau, Pascal, primary, Engle, Dannielle D., primary, Plenker, Dennis, primary, Deschênes, Astrid, primary, Somerville, Tim D. D., primary, Froeling, Fieke E. M., primary, Burkhart, Richard A., primary, Denroche, Robert E., primary, Jang, Gun-Ho, primary, Miyabayashi, Koji, primary, Young, C. Megan, primary, Patel, Hardik, primary, Ma, Michelle, primary, LaComb, Joseph F., primary, Palmaira, Randze Lerie D., primary, Javed, Ammar A., primary, Huynh, Jasmine C., primary, Johnson, Molly, primary, Arora, Kanika, primary, Robine, Nicolas, primary, Shah, Minita, primary, Sanghvi, Rashesh, primary, Goetz, Austin B., primary, Lowder, Cinthya Y., primary, Martello, Laura, primary, Driehuis, Else, primary, LeComte, Nicolas, primary, Askan, Gokce, primary, Iacobuzio-Donahue, Christine A., primary, Clevers, Hans, primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Thompson, Elizabeth, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Sasson, Aaron, primary, Kim, Joseph, primary, Wu, Maoxin, primary, Bucobo, Juan Carlos, primary, Allen, Peter, primary, Sejpal, Divyesh V., primary, Nealon, William, primary, Sullivan, James D., primary, Winter, Jordan M., primary, Gimotty, Phyllis A., primary, Grem, Jean L., primary, DiMaio, Dominick J., primary, Buscaglia, Jonathan M., primary, Grandgenett, Paul M., primary, Brody, Jonathan R., primary, Hollingsworth, Michael A., primary, O'Kane, Grainne M., primary, Notta, Faiyaz, primary, Kim, Edward, primary, Crawford, James M., primary, Devoe, Craig, primary, Ocean, Allyson, primary, Wolfgang, Christopher L., primary, Yu, Kenneth H., primary, Li, Ellen, primary, Vakoc, Christopher R., primary, Hubert, Benjamin, primary, Fischer, Sandra E., primary, Wilson, Julie M., primary, Moffitt, Richard, primary, Knox, Jennifer, primary, Krasnitz, Alexander, primary, Gallinger, Steven, primary, and Tuveson, David A., primary

Published
2023
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34. Data from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

Tiriac, Hervé, primary, Belleau, Pascal, primary, Engle, Dannielle D., primary, Plenker, Dennis, primary, Deschênes, Astrid, primary, Somerville, Tim D. D., primary, Froeling, Fieke E. M., primary, Burkhart, Richard A., primary, Denroche, Robert E., primary, Jang, Gun-Ho, primary, Miyabayashi, Koji, primary, Young, C. Megan, primary, Patel, Hardik, primary, Ma, Michelle, primary, LaComb, Joseph F., primary, Palmaira, Randze Lerie D., primary, Javed, Ammar A., primary, Huynh, Jasmine C., primary, Johnson, Molly, primary, Arora, Kanika, primary, Robine, Nicolas, primary, Shah, Minita, primary, Sanghvi, Rashesh, primary, Goetz, Austin B., primary, Lowder, Cinthya Y., primary, Martello, Laura, primary, Driehuis, Else, primary, LeComte, Nicolas, primary, Askan, Gokce, primary, Iacobuzio-Donahue, Christine A., primary, Clevers, Hans, primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Thompson, Elizabeth, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Sasson, Aaron, primary, Kim, Joseph, primary, Wu, Maoxin, primary, Bucobo, Juan Carlos, primary, Allen, Peter, primary, Sejpal, Divyesh V., primary, Nealon, William, primary, Sullivan, James D., primary, Winter, Jordan M., primary, Gimotty, Phyllis A., primary, Grem, Jean L., primary, DiMaio, Dominick J., primary, Buscaglia, Jonathan M., primary, Grandgenett, Paul M., primary, Brody, Jonathan R., primary, Hollingsworth, Michael A., primary, O'Kane, Grainne M., primary, Notta, Faiyaz, primary, Kim, Edward, primary, Crawford, James M., primary, Devoe, Craig, primary, Ocean, Allyson, primary, Wolfgang, Christopher L., primary, Yu, Kenneth H., primary, Li, Ellen, primary, Vakoc, Christopher R., primary, Hubert, Benjamin, primary, Fischer, Sandra E., primary, Wilson, Julie M., primary, Moffitt, Richard, primary, Knox, Jennifer, primary, Krasnitz, Alexander, primary, Gallinger, Steven, primary, and Tuveson, David A., primary

Published
2023
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35. Supplemental Figures from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

Tiriac, Hervé, primary, Belleau, Pascal, primary, Engle, Dannielle D., primary, Plenker, Dennis, primary, Deschênes, Astrid, primary, Somerville, Tim D. D., primary, Froeling, Fieke E. M., primary, Burkhart, Richard A., primary, Denroche, Robert E., primary, Jang, Gun-Ho, primary, Miyabayashi, Koji, primary, Young, C. Megan, primary, Patel, Hardik, primary, Ma, Michelle, primary, LaComb, Joseph F., primary, Palmaira, Randze Lerie D., primary, Javed, Ammar A., primary, Huynh, Jasmine C., primary, Johnson, Molly, primary, Arora, Kanika, primary, Robine, Nicolas, primary, Shah, Minita, primary, Sanghvi, Rashesh, primary, Goetz, Austin B., primary, Lowder, Cinthya Y., primary, Martello, Laura, primary, Driehuis, Else, primary, LeComte, Nicolas, primary, Askan, Gokce, primary, Iacobuzio-Donahue, Christine A., primary, Clevers, Hans, primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Thompson, Elizabeth, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Sasson, Aaron, primary, Kim, Joseph, primary, Wu, Maoxin, primary, Bucobo, Juan Carlos, primary, Allen, Peter, primary, Sejpal, Divyesh V., primary, Nealon, William, primary, Sullivan, James D., primary, Winter, Jordan M., primary, Gimotty, Phyllis A., primary, Grem, Jean L., primary, DiMaio, Dominick J., primary, Buscaglia, Jonathan M., primary, Grandgenett, Paul M., primary, Brody, Jonathan R., primary, Hollingsworth, Michael A., primary, O'Kane, Grainne M., primary, Notta, Faiyaz, primary, Kim, Edward, primary, Crawford, James M., primary, Devoe, Craig, primary, Ocean, Allyson, primary, Wolfgang, Christopher L., primary, Yu, Kenneth H., primary, Li, Ellen, primary, Vakoc, Christopher R., primary, Hubert, Benjamin, primary, Fischer, Sandra E., primary, Wilson, Julie M., primary, Moffitt, Richard, primary, Knox, Jennifer, primary, Krasnitz, Alexander, primary, Gallinger, Steven, primary, and Tuveson, David A., primary

Published
2023
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36. Supplementary Table S1-S4 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

Miyabayashi, Koji, primary, Baker, Lindsey A., primary, Deschênes, Astrid, primary, Traub, Benno, primary, Caligiuri, Giuseppina, primary, Plenker, Dennis, primary, Alagesan, Brinda, primary, Belleau, Pascal, primary, Li, Siran, primary, Kendall, Jude, primary, Jang, Gun Ho, primary, Kawaguchi, Risa Karakida, primary, Somerville, Tim D.D., primary, Tiriac, Hervé, primary, Hwang, Chang-Il, primary, Burkhart, Richard A., primary, Roberts, Nicholas J., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Gillis, Jesse, primary, Krasnitz, Alexander, primary, Vakoc, Christopher R., primary, Wigler, Michael, primary, Notta, Faiyaz, primary, Gallinger, Steven, primary, Park, Youngkyu, primary, and Tuveson, David A., primary

Published
2023
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37. Supplemental Table Legends from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

Tiriac, Hervé, primary, Belleau, Pascal, primary, Engle, Dannielle D., primary, Plenker, Dennis, primary, Deschênes, Astrid, primary, Somerville, Tim D. D., primary, Froeling, Fieke E. M., primary, Burkhart, Richard A., primary, Denroche, Robert E., primary, Jang, Gun-Ho, primary, Miyabayashi, Koji, primary, Young, C. Megan, primary, Patel, Hardik, primary, Ma, Michelle, primary, LaComb, Joseph F., primary, Palmaira, Randze Lerie D., primary, Javed, Ammar A., primary, Huynh, Jasmine C., primary, Johnson, Molly, primary, Arora, Kanika, primary, Robine, Nicolas, primary, Shah, Minita, primary, Sanghvi, Rashesh, primary, Goetz, Austin B., primary, Lowder, Cinthya Y., primary, Martello, Laura, primary, Driehuis, Else, primary, LeComte, Nicolas, primary, Askan, Gokce, primary, Iacobuzio-Donahue, Christine A., primary, Clevers, Hans, primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Thompson, Elizabeth, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Sasson, Aaron, primary, Kim, Joseph, primary, Wu, Maoxin, primary, Bucobo, Juan Carlos, primary, Allen, Peter, primary, Sejpal, Divyesh V., primary, Nealon, William, primary, Sullivan, James D., primary, Winter, Jordan M., primary, Gimotty, Phyllis A., primary, Grem, Jean L., primary, DiMaio, Dominick J., primary, Buscaglia, Jonathan M., primary, Grandgenett, Paul M., primary, Brody, Jonathan R., primary, Hollingsworth, Michael A., primary, O'Kane, Grainne M., primary, Notta, Faiyaz, primary, Kim, Edward, primary, Crawford, James M., primary, Devoe, Craig, primary, Ocean, Allyson, primary, Wolfgang, Christopher L., primary, Yu, Kenneth H., primary, Li, Ellen, primary, Vakoc, Christopher R., primary, Hubert, Benjamin, primary, Fischer, Sandra E., primary, Wilson, Julie M., primary, Moffitt, Richard, primary, Knox, Jennifer, primary, Krasnitz, Alexander, primary, Gallinger, Steven, primary, and Tuveson, David A., primary

Published
2023
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38. Supplementary Method SM1 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

Miyabayashi, Koji, primary, Baker, Lindsey A., primary, Deschênes, Astrid, primary, Traub, Benno, primary, Caligiuri, Giuseppina, primary, Plenker, Dennis, primary, Alagesan, Brinda, primary, Belleau, Pascal, primary, Li, Siran, primary, Kendall, Jude, primary, Jang, Gun Ho, primary, Kawaguchi, Risa Karakida, primary, Somerville, Tim D.D., primary, Tiriac, Hervé, primary, Hwang, Chang-Il, primary, Burkhart, Richard A., primary, Roberts, Nicholas J., primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Gillis, Jesse, primary, Krasnitz, Alexander, primary, Vakoc, Christopher R., primary, Wigler, Michael, primary, Notta, Faiyaz, primary, Gallinger, Steven, primary, Park, Youngkyu, primary, and Tuveson, David A., primary

Published
2023
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39. Supplemental Figure Legends from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

Tiriac, Hervé, primary, Belleau, Pascal, primary, Engle, Dannielle D., primary, Plenker, Dennis, primary, Deschênes, Astrid, primary, Somerville, Tim D. D., primary, Froeling, Fieke E. M., primary, Burkhart, Richard A., primary, Denroche, Robert E., primary, Jang, Gun-Ho, primary, Miyabayashi, Koji, primary, Young, C. Megan, primary, Patel, Hardik, primary, Ma, Michelle, primary, LaComb, Joseph F., primary, Palmaira, Randze Lerie D., primary, Javed, Ammar A., primary, Huynh, Jasmine C., primary, Johnson, Molly, primary, Arora, Kanika, primary, Robine, Nicolas, primary, Shah, Minita, primary, Sanghvi, Rashesh, primary, Goetz, Austin B., primary, Lowder, Cinthya Y., primary, Martello, Laura, primary, Driehuis, Else, primary, LeComte, Nicolas, primary, Askan, Gokce, primary, Iacobuzio-Donahue, Christine A., primary, Clevers, Hans, primary, Wood, Laura D., primary, Hruban, Ralph H., primary, Thompson, Elizabeth, primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Sasson, Aaron, primary, Kim, Joseph, primary, Wu, Maoxin, primary, Bucobo, Juan Carlos, primary, Allen, Peter, primary, Sejpal, Divyesh V., primary, Nealon, William, primary, Sullivan, James D., primary, Winter, Jordan M., primary, Gimotty, Phyllis A., primary, Grem, Jean L., primary, DiMaio, Dominick J., primary, Buscaglia, Jonathan M., primary, Grandgenett, Paul M., primary, Brody, Jonathan R., primary, Hollingsworth, Michael A., primary, O'Kane, Grainne M., primary, Notta, Faiyaz, primary, Kim, Edward, primary, Crawford, James M., primary, Devoe, Craig, primary, Ocean, Allyson, primary, Wolfgang, Christopher L., primary, Yu, Kenneth H., primary, Li, Ellen, primary, Vakoc, Christopher R., primary, Hubert, Benjamin, primary, Fischer, Sandra E., primary, Wilson, Julie M., primary, Moffitt, Richard, primary, Knox, Jennifer, primary, Krasnitz, Alexander, primary, Gallinger, Steven, primary, and Tuveson, David A., primary

Published
2023
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41. Supplementary Data from Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer

Author

Ponz-Sarvise, Mariano, primary, Corbo, Vincenzo, primary, Tiriac, Hervé, primary, Engle, Dannielle D., primary, Frese, Kristopher K., primary, Oni, Tobiloba E., primary, Hwang, Chang-Il, primary, Öhlund, Daniel, primary, Chio, Iok In Christine, primary, Baker, Lindsey A., primary, Filippini, Dea, primary, Wright, Kevin, primary, Bapiro, Tashinga E., primary, Huang, Pearl, primary, Smith, Paul, primary, Yu, Kenneth H., primary, Jodrell, Duncan I., primary, Park, Youngkyu, primary, and Tuveson, David A., primary

Published
2023
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42. Author Correction: Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

Author

Chan-Seng-Yue, Michelle, Kim, Jaeseung C., Wilson, Gavin W., Ng, Karen, Figueroa, Eugenia Flores, O’Kane, Grainne M., Connor, Ashton A., Denroche, Robert E., Grant, Robert C., McLeod, Jessica, Wilson, Julie M., Jang, Gun Ho, Zhang, Amy, Liang, Sheng-Ben, Borgida, Ayelet, Chadwick, Dianne, Kalimuthu, Sangeetha, Lungu, Ilinca, Bartlett, John M. S., Krzyzanowski, Paul M., Sandhu, Vandana, Tiriac, Hervé, Froeling, Fieke E. M., Karasinska, Joanna M., Topham, James T., Renouf, Daniel J., Schaeffer, David F., Jones, Steven J. M., Marra, Marco A., Laskin, Janessa, Chetty, Runjan, Stein, Lincoln D., Zogopoulos, George, Haibe-Kains, Benjamin, Campbell, Peter J., Tuveson, David A., Knox, Jennifer J., Fischer, Sandra E., Gallinger, Steven, and Notta, Faiyaz

Published
2020
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44. Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

Author

Sherman, Mara H., Yu, Ruth T., Engle, Dannielle D., Ding, Ning, Atkins, Annette R., Tiriac, Herve, Collisson, Eric A., Connor, Frances, Van Dyke, Terry, Kozlov, Serguei, Martin, Philip, Tseng, Tiffany W., Dawson, David W., Donahue, Timothy R., Masamune, Atsushi, Shimosegawa, Tooru, Apte, Minoti V., Wilson, Jeremy S., Ng, Beverly, Lau, Sue Lynn, Gunton, Jenny E., Wahl, Geoffrey M., Hunter, Tony, Drebin, Jeffrey A., O’Dwyer, Peter J., Liddle, Christopher, Tuveson, David A., Downes, Michael, and Evans, Ronald M.

Published
2014
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48. Characterization of a novel role for the Bur cyclin dependent kinase complex in pre-mRNA splicing

Author

Tiriac, Hervé

Subjects
UCSD Dissertations, Academic Biology. (Discipline), Dissertations Academic
Abstract

Pre-messenger RNA (pre-mRNA) splicing is carried out by a dynamic ribonucleoprotein machine called the spliceosome. From budding yeast to mammalian cells, the majority of splicing occurs cotranscriptionally. Such spatial and temporal coupling suggest coordinated regulation. To begin to understand this coupled regulation we must first identify factors that play functional roles both in transcription and in splicing, and elucidate their mechanism of action. This motivated a directed genetic screen to identify canonical transcription factors that affect splicing in vitro. Here we describe the discovery that the essential Saccharomyces cerevisiae cyclin dependent kinase Bur1/2, which has previously been shown to regulate transcription elongation, is necessary for efficient pre-mRNA splicing in vivo. Remarkably, the complex also plays a transcription-independent role in splicing that can be observed in vitro. Using in vitro spliceosome assembly assays we demonstrate that integrity of the Bur complex is essential for early prespliceosome formation as well as catalytic spliceosome formation and activation. Our data indicates that the Bur complex associates with prespliceosomes and interacts with the pre -mRNA substrate as well as the U1 snRNA. We further show that the Bur1 kinase can phosphorylate known splicing factors both in vitro as well as in extracts. Furthermore we show that the kinase likely mediates numerous phosphorylation events leading to phosphorylated protein in prespliceosomes and spliceosomes. Finally with the use of a modular analog sensitive Bur1 kinase we uncover a role for Bur1 activation through phosphorylation in spliceosome formation. These results provide the first example in budding yeast of a cyclin dependent kinase affecting pre-mRNA splicing and spliceosomal formation through physical interactions with the spliceosome. This highlights the importance of post translational modifications, and the proteins that mediate them, in regulating critical spliceosome rearrangements. Furthermore, our data paint a picture of a model whereby a transcription factor plays a previously uncharacterized and important regulatory role in pre-mRNA splicing, and hint at an intricate coupling mechanism between multiple RNA processes

Published
2011

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