Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution

Published on Jan 13, 2020in Nature Genetics27.603
· DOI :10.1038/S41588-019-0566-9
Michelle Chan-Seng-Yue18
Estimated H-index: 18
(OICR: Ontario Institute for Cancer Research),
J. Kim5
Estimated H-index: 5
(OICR: Ontario Institute for Cancer Research)
+ 38 AuthorsFaiyaz Notta22
Estimated H-index: 22
(OICR: Ontario Institute for Cancer Research)
Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression. Whole-genome sequencing, transcriptome sequencing and single-cell analysis of primary and metastatic pancreatic adenocarcinoma identify molecular subtypes and intratumor heterogeneity.
📖 Papers frequently viewed together
4,409 Citations
53 Citations
19 Authors (Chong Jin)
42 Citations
#1Stefanie Bärthel (DKFZ: German Cancer Research Center)H-Index: 2
#2Günter Schneider (TUM: Technische Universität München)H-Index: 47
Last. Dieter SaurH-Index: 60
view all 3 authors...
Epithelial differentiation of normal and tumor cells is orchestrated by lineage-determining transcriptional regulatory networks that enforce cell identity. Recent research by Kalisz et al (2020) in the EMBO Journal elucidates the molecular mechanisms by which a transcriptional differentiation program governed by HNF1A and KDM6A maintains acinar differentiation and the epithelial identity of pancreatic ductal adenocarcinoma (PDAC). Loss of function of either transcriptional regulator induces tumo...
2 CitationsSource
Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show different responses to the same therapeutic regimens. However, genomic analyses revealed quite a homogeneous disease picture, with very common mutations in four genes only (KRAS, TP53, CDKN2A, a...
8 CitationsSource
#1Madison H. Williams (University of Texas Health Science Center at San Antonio)H-Index: 1
#2Daruka Mahadevan (University of Texas Health Science Center at San Antonio)H-Index: 1
1 CitationsSource
#1Georgios Kaissis (Imperial College London)H-Index: 10
#2Sebastian Ziegelmayer (TUM: Technische Universität München)H-Index: 6
Last. Rickmer Braren (TUM: Technische Universität München)H-Index: 27
view all 15 authors...
To bridge the translational gap between recent discoveries of distinct molecular phenotypes of pancreatic cancer and tangible improvements in patient outcome, there is an urgent need to develop strategies and tools informing and improving the clinical decision process. Radiomics and machine learning approaches can offer non-invasive whole tumor analytics for clinical imaging data-based classification. The retrospective study assessed baseline computed tomography (CT) from 207 patients with prove...
15 CitationsSource
#1Matteo Ligorio (Harvard University)H-Index: 13
#2Srinjoy Sil (Harvard University)H-Index: 7
Last. David T. Ting (Harvard University)H-Index: 41
view all 48 authors...
Summary Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenc...
177 CitationsSource
#1Tim StuartH-Index: 12
#2Andrew Butler (NYU: New York University)H-Index: 14
Last. Rahul Satija (NYU: New York University)H-Index: 51
view all 10 authors...
Summary Single-cell transcriptomics has transformed our ability to characterize cell states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, a key analytical challenge is to integrate these datasets to better understand cellular identity and function. Here, we develop a strategy to "anchor" diverse datasets together, enabling us to integrate single-cell measurements not only across scRNA-seq techn...
3,424 CitationsSource
#1Ashton A. Connor (OICR: Ontario Institute for Cancer Research)H-Index: 15
#2Robert E. Denroche (OICR: Ontario Institute for Cancer Research)H-Index: 16
Last. Steven GallingerH-Index: 35
view all 45 authors...
Summary We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle re...
63 CitationsSource
#1Francesco Puleo (ULB: Université libre de Bruxelles)H-Index: 8
#2Rémy NicolleH-Index: 12
Last. Raphaël Maréchal (ULB: Université libre de Bruxelles)H-Index: 21
view all 19 authors...
Background & Aims Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. Methods ...
163 CitationsSource
#1Leland McInnesH-Index: 7
#2John HealyH-Index: 7
Last. Lukas GroßbergerH-Index: 1
view all 4 authors...
1,675 CitationsSource
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 chemothe...
333 CitationsSource
Cited By113
#1Teresa G Krieger (DKFZ: German Cancer Research Center)H-Index: 8
#2Solange Le Blanc (University Hospital Heidelberg)
Last. Roland Eils (DKFZ: German Cancer Research Center)H-Index: 98
view all 12 authors...
Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished ‘classical’ from ‘basal-like’ tumors with more aggressive clinical behavior. We derive PDAC organoids from 18 primary tumors and two matched liver metastases, and show that ‘classical’ and ‘basal-like’ cells coexist in individual organoids. By single-cell transcriptome analysis of PDAC organoids and primary PDAC, we identify distinct tum...
#1Joyce K. ThompsonH-Index: 1
#2Filip BednarH-Index: 18
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor’s intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic ...
Summary null Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, wh...
#1Rayane Dennaoui (WSU: Wayne State University)
#2Hridaya Shrestha (WSU: Wayne State University)H-Index: 4
Last. Kay Uwe Wagner (WSU: Wayne State University)H-Index: 63
view all 3 authors...
Although pancreatic cancer remains to be a leading cause of cancer-related deaths in many industrialized countries, there have been major advances in research over the past two decades that provided a detailed insight into the molecular and developmental processes that govern the genesis of this highly malignant tumor type. There is a continuous need for the development and analysis of preclinical and genetically engineered pancreatic cancer models to study the biological significance of new mol...
#1María Laura Gutiérrez (University of Salamanca)H-Index: 12
Last. Alberto Orfao (University of Salamanca)H-Index: 95
view all 3 authors...
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogene...
#1Makoto SanoH-Index: 13
#2Ryota Takahashi (UTokyo: University of Tokyo)H-Index: 25
Last. Kazuhiko Koike (UTokyo: University of Tokyo)H-Index: 91
view all 23 authors...
Objective Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer. Cancer-associated thrombosis/thromboembolism (CAT), frequently observed in PDAC, is known as a poor prognostic factor. Here, we investigated the underlying mechanisms between PDAC and CAT, and performed a trial of therapeutic approach for PDAC using a genetically engineered mouse model, PKF (Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox). Design Presence of CAT in PKF mice was detected by systemic autopsy. Plasma cytokines we...
6 CitationsSource
#1Wei Guo (SJTU: Shanghai Jiao Tong University)
#2Zhang Yuchao (Fudan University)
Last. Yufei Zhu (CAS: Chinese Academy of Sciences)H-Index: 12
view all 14 authors...
Despite the uniform mortality in pancreatic adenocarcinoma (PDAC), clinical disease heterogeneity exists with limited genomic differences. A highly aggressive tumor subtype termed 'basal-like' was identified to show worse outcomes and higher inflammatory responses. Here, we focus on the microbial effect in PDAC progression and present a comprehensive analysis of the tumor microbiome in different PDAC subtypes with resectable tumors using metagenomic sequencing. We found distinctive microbial com...
#1Shelize Khakoo (The Royal Marsden NHS Foundation Trust)H-Index: 5
#2Angelica Petrillo (Seconda Università degli Studi di Napoli)H-Index: 13
Last. Michele Ghidini (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico)H-Index: 23
view all 9 authors...
Pancreatic ductal adenocarcinoma (PDAC) has an aggressive tumor biology and is associated with poor survival outcomes. Most patients present with metastatic or locally advanced disease. In the 10–20% of patients with upfront resectable disease, surgery offers the only chance of cure, with the addition of adjuvant chemotherapy representing an established standard of care for improving outcomes. Despite resection followed by adjuvant chemotherapy, at best, 3-year survival reaches 63.4%. Post-opera...
Points cles L’incidence de l’adenocarcinome canalaire pancreatique (ACCP) est en hausse et selon les projections, il pourrait devenir la troisieme cause de deces par cancer au Canada[1][1]. Meme si on connait les facteurs de risque d’ACCP, la raison de cette incidence croissante est
#1Le Blanc (Charité)
#3Ishaque (MSD: Merck & Co.)
Last. Schuth (Heidelberg University)
view all 23 authors...
Abstract null Pancreatic ductal adenocarcinoma (PDAC) is characterized by high drug resistance and poor prognosis. Novel therapeutic and stratification strategies are urgently needed. Here, we present an integration of in-depth genomic and transcriptomic characterization with drug screening and clinical outcome based on a catalogue of 51 patient-derived tumor organoids (PDOs) from resected PDAC. Known PDAC molecular subtypes and their prognostic value are conserved in organoids. Integration of t...