A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.

Published on Apr 18, 2019in Cell38.637
· DOI :10.1016/J.CELL.2019.03.010
Nikki K. Lytle15
Estimated H-index: 15
(UCSD: University of California, San Diego),
L. Paige Ferguson2
Estimated H-index: 2
(UCSD: University of California, San Diego)
+ 30 AuthorsTannishtha Reya39
Estimated H-index: 39
Sources
Abstract
Summary Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
📖 Papers frequently viewed together
2 Citations
References74
Newest
#1Caroline Contat (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 3
#2Pierre-Benoit Ancey (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 4
Last. Etienne Meylan (EPFL: École Polytechnique Fédérale de Lausanne)H-Index: 27
view all 21 authors...
Glucose utilization increases in tumors, a metabolic process that is observed clinically by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss ...
3 CitationsSource
#1Krishna Sriram (UCSD: University of California, San Diego)H-Index: 16
#2Cristina Salmerón (UCSD: University of California, San Diego)H-Index: 13
Last. Paul A. Insel (UCSD: University of California, San Diego)H-Index: 107
view all 4 authors...
Pancreatic cancer has the highest mortality rate (5-year survival ~9%) among major types of malignant tumors. Pancreatic adenocarcinoma (PAAD) is the most common (>80%) and most lethal type of pancreatic cancer. A strong need thus exists for new approaches to treat PAAD. G protein-coupled receptors (GPCRs), the largest family of cell-surface receptors and drug targets, account for ~35% of approved drugs. Recent studies have revealed roles for GPCRs in PAAD cells and cells in the tumor microenvir...
6 CitationsSource
#1Lei Zhu (Heidelberg University)H-Index: 1
#1Lei Zhu (Heidelberg University)H-Index: 1
Last. Sebastian Schölch (Heidelberg University)H-Index: 15
view all 7 authors...
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most frequent cause of death from cancer. Circulating tumor cells (CTCs) with stem-like characteristics lead to distant metastases and thus contribute to the dismal prognosis of PDAC. Our purpose is to investigate the role of stemness in CTCs derived from a genetically engineered mouse model of PDAC and to further explore the potential molecular mechanisms. The publically available RNA sequencing dataset GSE51372 was analyzed, and CTCs with (...
5 CitationsSource
#1John Verigos (UoI: University of Ioannina)H-Index: 1
#1John VerigosH-Index: 3
Last. Angeliki MagklaraH-Index: 26
view all 8 authors...
Breast cancer is the leading cause of cancer death in the female population, despite advances in diagnosis and treatment. The highly heterogeneous nature of the disease represents a major obstacle to successful therapy and results in a significant number of patients developing drug resistance and, eventually, suffering from tumor relapse. Cancer stem cells (CSCs) are a small subset of tumor cells characterized by self-renewal, increased tumor-initiation capacity, and resistance to conventional t...
15 CitationsSource
#1Xiaoting Wang (Amgen)H-Index: 3
#1Xiaoting Wang (Amgen)H-Index: 7
Last. Sascha Rutz (Genentech)H-Index: 29
view all 4 authors...
: Members of the interleukin (IL)-10 family of cytokines play important roles in regulating immune responses during host defense but also in autoimmune disorders, inflammatory diseases, and cancer. Although IL-10 itself primarily acts on leukocytes and has potent immunosuppressive functions, other family members preferentially target nonimmune compartments, such as tissue epithelial cells, where they elicit innate defense mechanisms to control viral, bacterial, and fungal infections, protect tis...
41 CitationsSource
#1Martin Wartenberg (University of Bern)H-Index: 7
#2Silvia Cibin (University of Bern)H-Index: 2
Last. Evanthia Karamitopoulou (University of Bern)H-Index: 15
view all 11 authors...
Purpose: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC-cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. Experimental Design: A well-characterized PDAC-cohort (n=110) underwent next-generation sequencing with ...
69 CitationsSource
#1Sara Brin Rosenthal (UCSD: University of California, San Diego)H-Index: 15
#2Julia Len (UCSD: University of California, San Diego)H-Index: 2
Last. Kathleen M. Fisch (UCSD: University of California, San Diego)H-Index: 20
view all 6 authors...
Network biology is widely used to elucidate mechanisms of disease and biological processes. The ability to interact with biological networks is important for hypothesis generation and to give researchers an intuitive understanding of the data. We present visJS2jupyter, a tool designed to embed interactive networks in Jupyter notebooks to streamline network analysis and to promote reproducible research. The tool provides functions for performing and visualizing useful network operations in biolog...
11 CitationsSource
#1Philipp Spahn (UCSD: University of California, San Diego)H-Index: 12
#2Tyler Bath (UCSD: University of California, San Diego)H-Index: 3
Last. Olivier Harismendy (UCSD: University of California, San Diego)H-Index: 29
view all 7 authors...
Large-scale genetic screens using CRISPR/Cas9 technology have emerged as a major tool for functional genomics. With its increased popularity, experimental biologists frequently acquire large sequencing datasets for which they often do not have an easy analysis option. While a few bioinformatic tools have been developed for this purpose, their utility is still hindered either due to limited functionality or the requirement of bioinformatic expertise. To make sequencing data analysis of CRISPR/Cas...
31 CitationsSource
#1Jing Wang (BCM: Baylor College of Medicine)H-Index: 106
#2Suhas Vasaikar (BCM: Baylor College of Medicine)H-Index: 16
Last. Bing Zhang (BCM: Baylor College of Medicine)H-Index: 57
view all 5 authors...
Functional enrichment analysis has played a key role in the biological interpretation of high-throughput omics data. As a long-standing and widely used web application for functional enrichment analysis, WebGestalt has been constantly updated to satisfy the needs of biologists from different research areas. WebGestalt 2017 supports 12 organisms, 324 gene identifiers from various databases and technology platforms, and 150 937 functional categories from public databases and computational analyses...
580 CitationsSource
#1Harold Pimentel (University of California, Berkeley)H-Index: 15
#2Nicolas Bray (University of California, Berkeley)H-Index: 19
Last. Lior Pachter (California Institute of Technology)H-Index: 71
view all 5 authors...
We describe sleuth (http://pachterlab.github.io/sleuth), a method for the differential analysis of gene expression data that utilizes bootstrapping in conjunction with response error linear modeling to decouple biological variance from inferential variance. sleuth is implemented in an interactive shiny app that utilizes kallisto quantifications and bootstraps for fast and accurate analysis of data from RNA-seq experiments.
734 CitationsSource
Cited By39
Newest
#1Hongye Zou (UC Davis: University of California, Davis)
#2Nianxin Yang (UC Davis: University of California, Davis)
Last. Hongwu Chen (UC Davis: University of California, Davis)H-Index: 43
view all 4 authors...
Abstract null null Aberrant cholesterol metabolism and homeostasis in the form of elevated cholesterol biosynthesis and dysregulated efflux and metabolism is well recognized as a major feature of metabolic reprogramming in solid tumors. Recent studies have emphasized on major drivers and regulators such as Myc, mutant p53, SREBP2, LXRs and oncogenic signaling pathways that play crucial roles in tumor cholesterol metabolic reprogramming. Therapeutics such as statins targeting the mevalonate pathw...
Source
#1L. Paige Ferguson (UCSD: University of California, San Diego)H-Index: 2
#2Emily Diaz (UCSD: University of California, San Diego)H-Index: 1
Last. Tannishtha Reya (UCSD: University of California, San Diego)H-Index: 39
view all 3 authors...
Despite gains in knowledge of the intrinsic signals governing cancer progression, effective clinical management of cancer remains a challenge. Drug resistance and relapse, pose the greatest barriers to cancer care, and are often driven by the co-option of stem cell programs by subpopulations of aggressive cancer cells. Here, we focus on the role of the microenvironment in the acquisition and/or maintenance of stem cell states in cancer in the context of resistance and metastasis. We further disc...
Source
#1Hiroki Sato (Asahikawa Medical University)H-Index: 4
#2Andrew S. Liss (Harvard University)H-Index: 20
Last. Yusuke Mizukami (Asahikawa Medical University)H-Index: 39
view all 3 authors...
Pancreatic cancer currently has no subtypes that inform clinical decisions; hence, there exists an opportunity to rearrange the morphological and molecular taxonomy that guides a better understanding of tumor characteristics. Nonetheless, accumulating studies to date have revealed the large-duct type variant, a unique subtype of pancreatic ductal adenocarcinoma (PDA) with cystic features. This subtype often radiographically mimics intraductal papillary mucinous neoplasms (IPMNs) and involves mul...
Source
#1Zhengnan Yang (Sichuan University)H-Index: 3
#2Ryan C. Gimple (UCSD: University of California, San Diego)H-Index: 17
Last. Shengtao Zhou (Sichuan University)H-Index: 23
view all 6 authors...
Nuclear receptors are a family of transcription factors localized in cell nuclei, sensing specific ligands and fine-tuning a variety of cell physiological events. They have been intensively investigated in cancer biology. With their excellent properties of druggability and actionability, nuclear receptors have demonstrated much promise as novel therapeutic targets for different cancer types. Accumulating evidence has highlighted the essential roles of certain nuclear receptors in tumor immunolog...
1 CitationsSource
#1Timothy S. Strutzenberg (Scripps Research Institute)H-Index: 8
#2Scott J. NovickH-Index: 13
Last. Patrick R. GriffinH-Index: 85
view all 8 authors...
The retinoic acid receptor-related orphan receptor {gamma} (ROR{gamma}) is a ligand-dependent transcription factor of the nuclear receptor super family that underpins metabolic activity, immune function, and cancer progression. Despite being a valuable drug target in health and disease, our understanding of the ligand-dependent activities of ROR{gamma} is far from complete. Like most nuclear receptors, ROR{gamma} must recruit coregulatory protein to enact the ROR{gamma} target gene program. To d...
Source
#1Guohua Li (CSU: Central South University)H-Index: 3
#2Qiang Qu (CSU: Central South University)H-Index: 11
Last. Jian Qu (CSU: Central South University)H-Index: 15
view all 8 authors...
Although new developments of surgery, chemotherapy, radiotherapy, and immunotherapy treatments for cancer have improved patient survival, the emergence of chemoresistance in cancer has significant impacts on treatment effects. The development of chemoresistance involves several polygenic, progressive mechanisms at the molecular and cellular levels, as well as both genetic and epigenetic heterogeneities. Chemotherapeutics induce epigenetic reprogramming in cancer cells, converting a transient tra...
Source
#1Shaoheng Liang (Rice University)H-Index: 4
#2Vakul Mohanty (University of Texas MD Anderson Cancer Center)H-Index: 5
Last. Ken Chen (University of Texas MD Anderson Cancer Center)H-Index: 64
view all 9 authors...
A key challenge in studying organisms and diseases is to detect rare molecular programs and rare cell populations that drive development, differentiation and transformation. Molecular features, such as genes and proteins, defining rare cell populations are often unknown and are difficult to detect from unenriched single-cell data using conventional dimensionality reduction and clustering-based approaches. Here, we propose an unsupervised approach, SCMER (‘single-cell manifold-preserving feature ...
Source
#1Qiang Huang (Duke University)H-Index: 2
#2Aliesha Garrett (Duke University)H-Index: 6
Last. Xiling Shen (Duke University)H-Index: 23
view all 7 authors...
What you see is what you get-imaging techniques have long been essential for visualization and understanding of tissue development, homeostasis, and regeneration, which are driven by stem cell self-renewal and differentiation. Advances in molecular and tissue modeling techniques in the last decade are providing new imaging modalities to explore tissue heterogeneity and plasticity. Here we describe current state-of-the-art imaging modalities for tissue research at multiple scales, with a focus on...
1 CitationsSource
#1Alexander Semaan (University of Texas MD Anderson Cancer Center)H-Index: 8
#2Vincent Bernard (University of Texas MD Anderson Cancer Center)H-Index: 13
Last. Paola A. Guerrero (University of Texas MD Anderson Cancer Center)H-Index: 8
view all 16 authors...
Background Limited accessibility of the tumour precludes longitudinal characterisation for therapy guidance in pancreatic ductal adenocarcinoma (PDAC). Methods We utilised dielectrophoresis-field flow fractionation (DEP-FFF) to isolate circulating tumour cells (CTCs) in 272 blood draws from 74 PDAC patients (41 localised, 33 metastatic) to non-invasively monitor disease progression. Results Analysis using multiplex imaging flow cytometry revealed four distinct sub-populations of CTCs: epithelial...
1 CitationsSource
#1S. A. Saenz (BMS: Bristol-Myers Squibb)
view all 24 authors...
Retinoic acid receptor-related orphan nuclear receptor (ROR) {gamma}t is a member of the RORC nuclear hormone receptor family of transcription factors. ROR{gamma}t functions as a critical regulator of thymopoiesis and immune responses. ROR{gamma}t is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoim...
Source