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315 results on '"Laura D. Wood"'

1. Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms

Author

Ankit Chhoda, Anup Sharma, Bethsebie Sailo, Haoyu Tang, Nensi Ruzgar, Wan Ying Tan, Lee Ying, Rishabh Khatri, Anand Narayanan, Shrikant Mane, Bony De Kumar, Laura D. Wood, Christine Iacobuzio-Donahue, Christopher L. Wolfgang, John W. Kunstman, Ronald R. Salem, James J. Farrell, and Nita Ahuja

Subjects
Pancreatic cyst, Pancreatic cancer, Methylation-specific biomarker, Medicine, Genetics, QH426-470
Abstract

Abstract Background Intraductal papillary mucinous neoplasms (IPMNs), a type of cystic pancreatic cancer (PC) precursors, are increasingly identified on cross-sectional imaging and present a significant diagnostic challenge. While surgical resection of IPMN-related advanced neoplasia, i.e., IPMN-related high-grade dysplasia or PC, is an essential early PC detection strategy, resection is not recommended for IPMN-low-grade dysplasia (LGD) due to minimal risk of carcinogenesis, and significant procedural risks. Based on their promising results in prior validation studies targeting early detection of classical PC, DNA hypermethylation-based markers may serve as a biomarker for malignant risk stratification of IPMNs. This study investigates our DNA methylation-based PC biomarker panel (ADAMTS1, BNC1, and CACNA1G genes) in differentiating IPMN-advanced neoplasia from IPMN-LGDs. Methods Our previously described genome-wide pharmaco-epigenetic method identified multiple genes as potential targets for PC detection. The combination was further optimized and validated for early detection of classical PC in previous case–control studies. These promising genes were evaluated among micro-dissected IPMN tissue (IPMN-LGD: 35, IPMN-advanced neoplasia: 35) through Methylation-Specific PCR. The discriminant capacity of individual and combination of genes were delineated through Receiver Operating Characteristics curve analysis. Results As compared to IPMN-LGDs, IPMN-advanced neoplasia had higher hypermethylation frequency of candidate genes: ADAMTS1 (60% vs. 14%), BNC1 (66% vs. 3%), and CACGNA1G (25% vs. 0%). We observed Area Under Curve (AUC) values of 0.73 for ADAMTS1, 0.81 for BNC1, and 0.63 for CACNA1G genes. The combination of the BNC1/ CACNA1G genes resulted in an AUC of 0.84, sensitivity of 71%, and specificity of 97%. Combining the methylation status of the BNC1/CACNA1G genes, blood-based CA19-9, and IPMN lesion size enhanced the AUC to 0.92. Conclusion DNA-methylation based biomarkers have shown a high diagnostic specificity and moderate sensitivity for differentiating IPMN-advanced neoplasia from LGDs. Addition of specific methylation targets can improve the accuracy of the methylation biomarker panel and enable the development of noninvasive IPMN stratification biomarkers.

Published
2023
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2. Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion

Author

Yea Ji Jeong, Hildur Knutsdottir, Fatemeh Shojaeian, Michael G. Lerner, Maria F. Wissler, Elodie Henriet, Tammy Ng, Shalini Datta, Bernat Navarro-Serer, Peter Chianchiano, Benedict Kinny-Köster, Jacquelyn W. Zimmerman, Genevieve Stein-O’Brien, Matthias M. Gaida, James R. Eshleman, Ming-Tseh Lin, Elana J. Fertig, Andrew J. Ewald, Joel S. Bader, and Laura D. Wood

Subjects
Gastroenterology, Oncology, Medicine
Abstract

Pancreatic ductal adenocarcinoma (PDAC) frequently presents with metastasis, but the molecular programs in human PDAC cells that drive invasion are not well understood. Using an experimental pipeline enabling PDAC organoid isolation and collection based on invasive phenotype, we assessed the transcriptomic programs associated with invasion in our organoid model. We identified differentially expressed genes in invasive organoids compared with matched noninvasive organoids from the same patients, and we confirmed that the encoded proteins were enhanced in organoid invasive protrusions. We identified 3 distinct transcriptomic groups in invasive organoids, 2 of which correlated directly with the morphological invasion patterns and were characterized by distinct upregulated pathways. Leveraging publicly available single-cell RNA-sequencing data, we mapped our transcriptomic groups onto human PDAC tissue samples, highlighting differences in the tumor microenvironment between transcriptomic groups and suggesting that non-neoplastic cells in the tumor microenvironment can modulate tumor cell invasion. To further address this possibility, we performed computational ligand-receptor analysis and validated the impact of multiple ligands (TGF-β1, IL-6, CXCL12, MMP9) on invasion and gene expression in an independent cohort of fresh human PDAC organoids. Our results identify molecular programs driving morphologically defined invasion patterns and highlight the tumor microenvironment as a potential modulator of these programs.

Published
2023
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4. Genomic characterization of malignant progression in neoplastic pancreatic cysts

Author

Michaël Noë, Noushin Niknafs, Catherine G. Fischer, Wenzel M. Hackeng, Violeta Beleva Guthrie, Waki Hosoda, Marija Debeljak, Eniko Papp, Vilmos Adleff, James R. White, Claudio Luchini, Antonio Pea, Aldo Scarpa, Giovanni Butturini, Giuseppe Zamboni, Paola Castelli, Seung-Mo Hong, Shinichi Yachida, Nobuyoshi Hiraoka, Anthony J. Gill, Jaswinder S. Samra, G. Johan A. Offerhaus, Anne Hoorens, Joanne Verheij, Casper Jansen, N. Volkan Adsay, Wei Jiang, Jordan Winter, Jorge Albores-Saavedra, Benoit Terris, Elizabeth D. Thompson, Nicholas J. Roberts, Ralph H. Hruban, Rachel Karchin, Robert B. Scharpf, Lodewijk A. A. Brosens, Victor E. Velculescu, and Laura D. Wood

Subjects
Science
Abstract

Neoplastic pancreatic cysts are associated with invasive pancreatic cancer, but their origins and evolutionary relationships are unclear. Here, the authors present the evolutionary analysis of neoplastic cysts and report them as precursors of invasive pancreatic cancer, and that SMAD4/TGFBR2 alterations are likely drivers of invasion in a subset of cases.

Published
2020
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5. Telomere alterations in neurofibromatosis type 1-associated solid tumors

Author

Fausto J. Rodriguez, Mindy K. Graham, Jacqueline A. Brosnan-Cashman, John R. Barber, Christine Davis, M. Adelita Vizcaino, Doreen N. Palsgrove, Caterina Giannini, Melike Pekmezci, Sonika Dahiya, Murat Gokden, Michael Noë, Laura D. Wood, Christine A. Pratilas, Carol D. Morris, Allan Belzberg, Jaishri Blakeley, and Christopher M. Heaphy

Subjects
NF1, ATRX, Alternative lengthening of telomeres, Glioma, MPNST, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p

Published
2019
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6. Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood

Author

Maryam A. L. Eissa, Lane Lerner, Eihab Abdelfatah, Nakul Shankar, Joseph K. Canner, Nesrin M. Hasan, Vesal Yaghoobi, Barry Huang, Zachary Kerner, Felipe Takaesu, Christopher Wolfgang, Ruby Kwak, Michael Ruiz, Matthew Tam, Thomas R. Pisanic, Christine A. Iacobuzio-Donahue, Ralph H. Hruban, Jin He, Tza-Huei Wang, Laura D. Wood, Anup Sharma, and Nita Ahuja

Subjects
Cell-free DNA, MOB, ADAMTS1, BNC1, Methylation, Biomarker, Medicine, Genetics, QH426-470
Abstract

Abstract Background Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer. Results Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71–0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63–0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77–0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90–0.98) compared to 57.1% for CA 19-9 alone. Conclusion The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.

Published
2019
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7. High grade serous ovarian carcinomas originate in the fallopian tube

Author

S. Intidhar Labidi-Galy, Eniko Papp, Dorothy Hallberg, Noushin Niknafs, Vilmos Adleff, Michael Noe, Rohit Bhattacharya, Marian Novak, Siân Jones, Jillian Phallen, Carolyn A. Hruban, Michelle S. Hirsch, Douglas I. Lin, Lauren Schwartz, Cecile L. Maire, Jean-Christophe Tille, Michaela Bowden, Ayse Ayhan, Laura D. Wood, Robert B. Scharpf, Robert Kurman, Tian-Li Wang, Ie-Ming Shih, Rachel Karchin, Ronny Drapkin, and Victor E. Velculescu

Subjects
Science
Abstract

It has previously been proposed that high-grade serous ovarian carcinoma (HGSOC) may originate from the fallopian tube. Here, the authors analyze genetic aberrances in fallopian tube lesions, ovarian cancers, and metastases from HGSOC patients and establish the evolutionary origins of HGSOC in the fallopian tube.

Published
2017
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8. Genomic Landscapes of Pancreatic Neoplasia

Author

Laura D. Wood and Ralph H. Hruban

Subjects
Pancreatic neoplasms, Cancer genomics, Cancer mutation, Pathology, RB1-214
Abstract

Pancreatic cancer is a deadly disease with a dismal prognosis. However, recent advances in sequencing and bioinformatic technology have led to the systematic characterization of the genomes of all major tumor types in the pancreas. This characterization has revealed the unique genomic landscape of each tumor type. This knowledge will pave the way for improved diagnostic and therapeutic approaches to pancreatic tumors that take advantage of the genetic alterations in these neoplasms.

Published
2015
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10. Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance

Author

Hirokazu Kimura, Raymond M Paranal, Neha Nanda, Laura D Wood, James R Eshleman, Ralph H Hruban, Michael G Goggins, Alison P Klein, The Familial Pancreatic Cancer Genome Sequencing Project, and Nicholas J Roberts

Subjects
pancreas, cancer, familial cancer, CDKN2A, variant of uncertain significance, pancreatic ductal adenocarcinoma, Medicine, Science, Biology (General), QH301-705.5
Abstract

Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. Twenty-nine germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. Twelve of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.

Published
2022
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11. Contributors

Author

Daniela S. Allende, Lodewjk A.A. Brosens, Michael Cruise, James Conner, Leona Doyle, Ilyssa O. Gordon, Catherine Hagen, Bence Kövari, Gregory Y. Lauwers, Mikhail Lisovsky, Mari Mino-Kenudson, Reetesh K. Pai, Rish Pai, Nicole C. Panarelli, David Papke, Deepa T. Patil, Scott Robertson, Safia Nawazish Salaria, Amitabh Srivastava, Sarah E. Umetsu, Kwun Wah Wen, Laura D. Wood, and Lisa M. Yerian

Published
2024

13. Tissue clearing and 3D reconstruction of digitized, serially sectioned slides provide novel insights into pancreatic cancer

Author

Ashley L. Kiemen, Alexander Ioannis Damanakis, Alicia M. Braxton, Jin He, Daniel Laheru, Elliot K. Fishman, Patrick Chames, Cristina Almagro Pérez, Pei-Hsun Wu, Denis Wirtz, Laura D. Wood, Ralph H. Hruban, Johns Hopkins University (JHU), University Hospital of Cologne [Cologne], Johns Hopkins University School of Medicine [Baltimore], Aix Marseille Université (AMU), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)

Subjects
clearing, machine learning, CODA, [SDV]Life Sciences [q-bio], Pancreatic cancer, General Medicine, artificial intelligence, digital pathology, three dimensions
Abstract

International audience; Pancreatic cancer is currently the third leading cause of cancer death in the United States. The clinical hallmarks of this disease include abdominal pain that radiates to the back, the presence of a hypoenhancing intrapancreatic lesion on imaging, and widespread liver metastases. Technologies such as tissue clearing and three-dimensional (3D) reconstruction of digitized serially sectioned hematoxylin and eosin stained slides, can be used to visualize large (up to two to three-centimeter cube) tissues at cellular resolution. When applied to human pancreatic cancers, these 3D visualization techniques have provided novel insights into the basis of a number of the clinical hallmarks of this disease. Here we describe the clinical features of pancreatic cancer, review techniques for clearing and the 3D reconstruction of digitized microscope slides, and provide examples that illustrate how 3D visualization of human pancreatic cancer at the microscopic level has closed the gap between bench and bedside. Compared to animal models and 2D microscopy, studies of human tissues in 3D can reveal the difference between what can happen and what does happen in human cancers.

Published
2023

14. CODA: quantitative 3D reconstruction of large tissues at cellular resolution

Author

Ashley L. Kiemen, Alicia M. Braxton, Mia P. Grahn, Kyu Sang Han, Jaanvi Mahesh Babu, Rebecca Reichel, Ann C. Jiang, Bridgette Kim, Jocelyn Hsu, Falone Amoa, Sashank Reddy, Seung-Mo Hong, Toby C. Cornish, Elizabeth D. Thompson, Peng Huang, Laura D. Wood, Ralph H. Hruban, Denis Wirtz, and Pei-Hsun Wu

Subjects
Cell Biology, Molecular Biology, Biochemistry, Biotechnology
Published
2022

16. Data from Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Author

Tatsuhiro Shibata, Ralph H. Hruban, Laura D. Wood, Lodewijk A.A. Brosens, Tohru Kiyono, Toshiro Sato, Toru Furukawa, Koji Arihiro, Chigusa Morizane, Hiroki Yamaue, Masakazu Yamamoto, Keiichi Okano, Tomoyuki Okumura, Wenzel M. Hackeng, Minoru Oshima, Ayaka Shimomura, So Takata, Hidenori Tanaka, Mitsuro Kanda, Shuichi Mitsunaga, Taiki Hashimoto, Hirofumi Rokutan, Yasuhito Arai, Eisaku Furukawa, Mamoru Kato, Satoshi Shiba, Seiko Hirono, Ryota Higuchi, Natsuko Hama, Erina Takai, Masami Suzuki, Mihoko Saito-Adachi, Hiromi Nakamura, Kenta Kawasaki, Masafumi Horie, Yoichiro Nakatani, Michaël Noë, Yasushi Totoki, and Shinichi Yachida

Abstract

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.Significance:GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic and epigenomic features.This article is highlighted in the In This Issue feature, p. 587

Published
2023

17. Supplementary Data from Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Author

Tatsuhiro Shibata, Ralph H. Hruban, Laura D. Wood, Lodewijk A.A. Brosens, Tohru Kiyono, Toshiro Sato, Toru Furukawa, Koji Arihiro, Chigusa Morizane, Hiroki Yamaue, Masakazu Yamamoto, Keiichi Okano, Tomoyuki Okumura, Wenzel M. Hackeng, Minoru Oshima, Ayaka Shimomura, So Takata, Hidenori Tanaka, Mitsuro Kanda, Shuichi Mitsunaga, Taiki Hashimoto, Hirofumi Rokutan, Yasuhito Arai, Eisaku Furukawa, Mamoru Kato, Satoshi Shiba, Seiko Hirono, Ryota Higuchi, Natsuko Hama, Erina Takai, Masami Suzuki, Mihoko Saito-Adachi, Hiromi Nakamura, Kenta Kawasaki, Masafumi Horie, Yoichiro Nakatani, Michaël Noë, Yasushi Totoki, and Shinichi Yachida

Abstract

Supplementary Data from Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Published
2023

18. Supplementary Figure S1 from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes

Author

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

Abstract

Comparison of IGO- and OGO-derived lesions

Published
2023

19. Figure S4 from Cell of Origin Influences Pancreatic Cancer Subtype

Author

Laura D. Attardi, Laura D. Wood, Christina Curtis, Hannes Vogel, Jose A. Seoane, Kathryn J. Hanson, Abigail S. Mulligan, Hang Xu, and Brittany M. Flowers

Abstract

Transcriptome and histological analysis of mouse acinar and ductal cell-derived tumors

Published
2023

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

Author

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

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
2023

21. Table S1 from Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Author

Nishant Agrawal, Patrick K. Ha, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Carole Fakhry, Shizhang Ling, Michael Considine, Luigi Marchionni, Sarah J. Wheelan, Elana J. Fertig, Rachel Karchin, Noushin Niknafs, Collin Tokheim, Laura D. Wood, Justin A. Bishop, Sian Jones, Mark Sausen, C. Conover Talbot, and Eleni M. Rettig

Abstract

Summary of sequence analysis of adenoid cystic carcinoma.

Published
2023

22. Supplemental Figures from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

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

Abstract

Supplemental Figures

Published
2023

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

Author

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

Abstract

Confocal z-stack imaging of immunofluorescent (IF) images of mStrawberry-hT3 grafts 4 weeks after IGO transplantation

Published
2023

24. Table S3 from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

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

Abstract

Table S3

Published
2023

25. Supplementary Tables S1 - S12 from Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

Author

Alison P. Klein, Ralph H. Hruban, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, James R. Eshleman, Rachel Karchin, Michael Goggins, Peter P. Zandi, Laura D. Wood, Christopher L. Wolfgang, Yuxuan Wang, Alyssa L. Smith, Andrew D. Rhim, James B. Potash, Mehdi Pirooznia, Jennifer Parla, Noushin Niknafs, K. Wyatt McMahon, Richard W. McCombie, Alvin Makohon-Moore, Melissa Kramer, Christine Iacobuzio-Donahue, Joseph M. Herman, Fernando S. Goes, Christopher Douville, Erica J. Childs, Michele L. Cote, Yun-Ching Chen, Kari G. Chaffee, Jennifer Axilbund, Syed Z. Ali, George Zogopoulos, Sapna Syngal, Elena Stoffel, Ann G. Schwartz, Anil K. Rustgi, Sara H. Olson, Robert C. Kurtz, Steven Gallinger, Randall Brand, Melissa L. Bondy, Gloria M. Petersen, Alexis L. Norris, and Nicholas J. Roberts

Abstract

Supplementary Tables S1 - S12. Supplementary Table S1. Prioritization of candidate FPC susceptibility genes by private heterozygous PTVs. Supplementary Table S2. FPC patients harboring a private PTVs ASXL1, DNMT3A, and TET2. Supplementary Table S3. 87 genes analyzed in-depth in FPC patients and kindreds. Supplementary Table S4. Deleterious variants in FPC patients and kindreds. Supplementary Table S5. FPC samples with more than one deleterious variant. Supplementary Table S6. Deleterious variants in BCCS samples. Supplementary Table S7. Deleterious variants in FPC kindreds and BCCS samples. Supplementary Table S8. Differences in deleterious variants between FPC kindreds with three or more affected members and BCCS samples. Supplementary Table S9. Private heterozygous PTVs present in all sequenced affected members of a kindred. Supplementary Table S10. Deleterious variants shared between affected members of an FPC kindred. Supplementary Table S11. Somatic mutations in FPC patient tumors. Supplementary Table S12. Summary of somatic mutation data for FPC patient tumors by gene.

Published
2023

27. Data from Cell of Origin Influences Pancreatic Cancer Subtype

Author

Laura D. Attardi, Laura D. Wood, Christina Curtis, Hannes Vogel, Jose A. Seoane, Kathryn J. Hanson, Abigail S. Mulligan, Hang Xu, and Brittany M. Flowers

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell–derived and acinar cell–derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution.Significance:Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention.This article is highlighted in the In This Issue feature, p. 521

Published
2023

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

Author

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

Abstract

Supplementary Table S1 Survival times of IGO and OGO mice Supplementary Table S2 Characteristics of patient-derived organoids, including KRAS, TP53, SMAD4, CDKN2A mutation status and patient stage Supplementary Table S3 Summary of Survival Data, including engraftment rate, mean survival, metastatic frequency Supplementary Table S4 Primers for quantitative PCR

Published
2023

29. Figure S2 from Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Author

Nishant Agrawal, Patrick K. Ha, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Carole Fakhry, Shizhang Ling, Michael Considine, Luigi Marchionni, Sarah J. Wheelan, Elana J. Fertig, Rachel Karchin, Noushin Niknafs, Collin Tokheim, Laura D. Wood, Justin A. Bishop, Sian Jones, Mark Sausen, C. Conover Talbot, and Eleni M. Rettig

Abstract

Axonal guidance signaling pathway alterations in adenoid cystic carcinoma.

Published
2023

30. Supplementary Data from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Christine A. Iacobuzio-Donahue, Barry S. Taylor, Nicholas D. Socci, Martin A. Nowak, Ralph H. Hruban, Laura D. Wood, Eileen M. O'Reilly, Debyani Chakravarty, Mithat Gönen, Alexander V. Penson, Craig M. Bielski, Alexander Heyde, Johannes G. Reiter, Jerry P. Melchor, Lance Zhang, Rajya Kappagantula, Jungeui Hong, Akimasa Hayashi, Alvin P. Makohon-Moore, Jeffrey M. Gerold, Marc A. Attiyeh, and Hitomi Sakamoto

Abstract

Figures S1-S3

Published
2023

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

Author

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

Abstract

Method Used to Define the Thresholds for Fast- and Slow-Progressing IGO-Derived Tumors

Published
2023

32. Supplemental Table Legends from Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

Author

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

Abstract

Supplemental Table Legends

Published
2023

33. Tables S1-S8 from The Evolutionary Origins of Recurrent Pancreatic Cancer

Author

Christine A. Iacobuzio-Donahue, Barry S. Taylor, Nicholas D. Socci, Martin A. Nowak, Ralph H. Hruban, Laura D. Wood, Eileen M. O'Reilly, Debyani Chakravarty, Mithat Gönen, Alexander V. Penson, Craig M. Bielski, Alexander Heyde, Johannes G. Reiter, Jerry P. Melchor, Lance Zhang, Rajya Kappagantula, Jungeui Hong, Akimasa Hayashi, Alvin P. Makohon-Moore, Jeffrey M. Gerold, Marc A. Attiyeh, and Hitomi Sakamoto

Abstract

Supplemental Tables

Published
2023

34. Supplementary Video 5 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Supplementary Video 5. Time-lapse analysis of SMAD4-mutant PDAC organoids: Dox-TGFβ-.

Published
2023

35. Data from Circulating Tumor Cells Expressing Markers of Tumor-Initiating Cells Predict Poor Survival and Cancer Recurrence in Patients with Pancreatic Ductal Adenocarcinoma

Author

Laura D. Wood, Christopher L. Wolfgang, Zeshaan A. Rasheed, Michael Goggins, Jin He, John L. Cameron, Matthew J. Weiss, Amanda L. Blackford, and Katherine E. Poruk

Abstract

Purpose: Circulating tumor cells (CTCs) have been identified in the blood of patients with pancreatic adenocarcinoma (PDAC), but little is known about the exact phenotype of these cells. We assessed expression of aldehyde dehydrogenase (ALDH), CD133, and CD44 as markers of CTCs with a tumor-initiating cell (TIC) phenotype in patients with PDAC and the relationship of this expression to patient outcomes.Experimental Design: Peripheral blood from 60 consecutive patients with PDAC undergoing surgical resection was obtained and processed using the Isolation by Size of Epithelial Tumor (ISET) method. Immunofluorescence was used to identify CTCs expressing cytokeratin, CD133, CD44, and ALDH.Results: Forty-seven patients (78%) had epithelial CTCs staining positive for pan-cytokeratin and at least one TIC marker. Forty-six patients (77%) had epithelial CTCs that labeled with antibodies to cytokeratin and ALDH. By separate analysis, 34 (57%) had cytokeratin-positive, CD133-positive, and CD44-positive (triple-positive) CTCs, whereas 40 (67%) had cytokeratin-positive, CD133-positive, CD44-negative CTCs. The remaining 13 patients did not have CTCs, as defined by cytokeratin expression. ALDH-positive CTCs and triple-positive CTCs were significantly associated with worse survival by univariate analysis, even when accounting for other significant prognostic factors (all, P ≤ 0.01). ALDH-positive CTCs, triple-positive CTCs, and dual cytokeratin- and CD133-positive CTCs were independent predictors of tumor recurrence by logistic regression analysis and associated with decreased disease-free survival (all, P ≤ 0.03).Conclusions: CTCs labeling with one or more markers of TICs are found in a majority of patients with PDAC and are independently predictive of decreased disease-free and overall survival. Clin Cancer Res; 23(11); 2681–90. ©2016 AACR.

Published
2023

36. Supplementary Figure 1 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

SOX9 expression in PDAC organoids

Published
2023

37. Supplementary Video 6 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Supplementary Video 6. Time-lapse analysis of SMAD4-mutant PDAC organoids: Dox+TGFβ-.

Published
2023

38. Data from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4-mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4-mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in SMAD4-mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss.Significance:Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4-mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism.

Published
2023

39. Supplementary Figure 5 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Association Between SMAD4 Status and Recurrence/Death

Published
2023

41. Data from Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis

Author

Laura D. Wood, Anirban Maitra, Ralph H. Hruban, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Amanda Blackford, Christopher L. Wolfgang, Neda Rezaee, Niki A. Ottenhof, Roeland F. de Wilde, Ming Zhang, and Marco Dal Molin

Abstract

Purpose: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently Experimental Design: We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs.Results: KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival.Conclusions: Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC. Clin Cancer Res; 21(8); 1944–50. ©2015 AACR.

Published
2023

42. Supplementary Materials from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

List of Supplementary Materials

Published
2023

43. Supplementary Video 4 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Supplementary Video 4. Collective invasion in PDAC organoid cultured in collagen I.

Published
2023

45. Supplementary Table 3 from Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis

Author

Laura D. Wood, Anirban Maitra, Ralph H. Hruban, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Amanda Blackford, Christopher L. Wolfgang, Neda Rezaee, Niki A. Ottenhof, Roeland F. de Wilde, Ming Zhang, and Marco Dal Molin

Abstract

Supplementary Table 3. Somatic mutations in targeted sequencing from Validation Set

Published
2023

46. Supplementary Video 2 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Supplementary Video 2. Mesenchymal invasion in PDAC organoid cultured in collagen I (focal invasion).

Published
2023

47. Supplementary Table 1 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Clinical and Pathological Features of Resected PDACs Analyzed in Organoid Culture

Published
2023

48. Supplementary Table 3 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome

Author

Laura D. Wood, Andrew J. Ewald, Nicholas J. Roberts, Elizabeth D. Thompson, Michael G. Goggins, Christopher L. Wolfgang, Jin He, Richard A. Burkhart, Stefan Heinrich, Matthias M. Gaida, Randall E. Brand, Amer H. Zureikat, Aatur D. Singhi, Steven Gallinger, Sandra E. Fischer, A. Floortje van Oosten, Alina Hasanain, Vincent P. Groot, Neil M. Neumann, Kim-Vy Nguyen-Ngoc, Kohei Fujikura, Danielle Jones, Gemma Lionheart, Anne M. Macgregor-Das, Michael J. Pflüger, Bo Huang, Maria A. Trujillo, Tammy Ng, Cameron Dowiak, Nicola Veronese, Claudio Luchini, Limin Xia, Peter Chianchiano, Yea Ji Jeong, Bernat Navarro-Serer, and Wenjie Huang

Abstract

Sequencing Data Quality from Primary FFPE PDAC Samples

Published
2023

49. Supplementary Table 2 from Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis

Author

Laura D. Wood, Anirban Maitra, Ralph H. Hruban, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Amanda Blackford, Christopher L. Wolfgang, Neda Rezaee, Niki A. Ottenhof, Roeland F. de Wilde, Ming Zhang, and Marco Dal Molin

Abstract

Supplementary Table 2. Somatic mutations identified in exome sequencing of VLTSs

Published
2023

50. Supplementary Table 1 from Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis

Author

Laura D. Wood, Anirban Maitra, Ralph H. Hruban, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Amanda Blackford, Christopher L. Wolfgang, Neda Rezaee, Niki A. Ottenhof, Roeland F. de Wilde, Ming Zhang, and Marco Dal Molin

Abstract

Supplementary Table 1. Summary of exome sequencing data for VLTSs

Published
2023

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