Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15
Animals
B7-H1 Antigen
/ antagonists & inhibitors
Cancer-Associated Fibroblasts
/ drug effects
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Cell Lineage
/ genetics
Clinical Trials as Topic
Computational Biology
Disease Models, Animal
Drug Resistance, Neoplasm
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Membrane Proteins
/ metabolism
Mice
Myofibroblasts
/ drug effects
Pancreatic Neoplasms
/ drug therapy
RNA-Seq
Single-Cell Analysis
Transforming Growth Factor beta
/ metabolism
Treatment Outcome
Tumor Microenvironment
/ drug effects
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
05
06
2019
revised:
24
09
2019
accepted:
04
11
2019
pubmed:
9
11
2019
medline:
30
1
2021
entrez:
9
11
2019
Statut:
ppublish
Résumé
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15
Identifiants
pubmed: 31699795
pii: 2159-8290.CD-19-0644
doi: 10.1158/2159-8290.CD-19-0644
doi:
Substances chimiques
B7-H1 Antigen
0
CD274 protein, human
0
Immune Checkpoint Inhibitors
0
LRRC15 protein, human
0
Membrane Proteins
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
232-253Informations de copyright
©2019 American Association for Cancer Research.
Références
Stark AP, Sacks GD, Rochefort MM, Donahue TR, Reber HA, Tomlinson JS, et al. Long-term survival in patients with pancreatic ductal adenocarcinoma. Surgery. 2016;159:1520–7.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein–α. Science. 2010;330:827–30.
Lo A, Wang L-CS, Scholler J, Monslow J, Avery D, Newick K, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015;75:2800–10.
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2015;28:831–3.
Santos AM, Jung J, Aziz N, Kissil JL, Puré E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 2009;119:3613–25.
Wang L-CS, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66.
LeBleu VS, Kalluri R. A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis Model Mech. 2018;11:dmm029447.
Avery D, Govindaraju P, Jacob M, Todd L, Monslow J, Puré E. Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts. Matrix Biol. 2018;67:90–106.
Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33:463–79.
Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110:20212–7.
Apte M, Haber P, Applegate T, Norton I, McCaughan G, Korsten M, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43:128–33.
Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003;17:3112–26.
Chung W-J, Daemen A, Cheng JH, Long JE, Cooper JE, Wang B, et al. Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous. Proc Natl Acad Sci U S A. 2017;114:E10947–55.
Hruban RH, Adsay VN, Albores-Saavedra J, Anver MR, Biankin AV, Boivin GP, et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 2006;66:95–106.
Erkan M, Reiser-Erkan C, Michalski CW, Deucker S, Sauliunaite D, Streit S, et al. Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia. 2009;11:497–508.
Buechler MB, Kim K-W, Onufer EJ, Williams JW, Little CC, Dominguez CX, et al. A stromal niche defined by expression of the transcription factor WT1 mediates programming and homeostasis of cavity-resident macrophages. Immunity. 2019;51:119–30.
Cremasco V, Astarita JL, Grauel AL, Keerthivasan S, MacIsaac KD, Woodruff MC, et al. FAP delineates heterogeneous and functionally divergent stromal cells in immune-excluded breast tumors. Cancer Immunol Res. 2018;6:1472–85.
Xie T, Wang Y, Deng N, Huang G, Taghavifar F, Geng Y, et al. Single-cell deconvolution of fibroblast heterogeneity in mouse pulmonary fibrosis. Cell Rep. 2018;22:3625–40.
Street K, Risso D, Fletcher RB, Das D, Ngai J, Yosef N, et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018;19:477.
Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3:422–33.
Groulx J-F, Gagné D, Benoit YD, Martel D, Basora N, Beaulieu J-F. Collagen VI is a basement membrane component that regulates epithelial cell–fibronectin interactions. Matrix Biol. 2011;30:195–206.
Steele CW, Karim SA, Leach J, Bailey P, Upstill-Goddard R, Rishi L, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29:832–45.
Sano M, Ijichi H, Takahashi R, Miyabayashi K, Fujiwara H, Yamada T, et al. Blocking CXCLs–CXCR2 axis in tumor–stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment. Oncogenesis. 2019;8:8.
Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL. IFNγ and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 2016;6:400–13.
Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer. 2017;17:38.
Goel H, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13:871–82.
Liang M, Ma Q, Ding N, Luo F, Bai Y, Kang F, et al. IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis. Cell Death Dis. 2019;10:353.
Shi Y, Gao W, Lytle NK, Huang P, Yuan X, Dann AM, et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature. 2019;569:131–5.
Pietras K, Sjöblom T, Rubin K, Heldin C-H, Östman A. PDGF receptors as cancer drug targets. Cancer Cell. 2003;3:439–43.
D'Costa Z, Jones K, Azad A, van Stiphout R, Lim SY, Gomes AL, et al. Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer. Cancer Res. 2017;77:5952–62.
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur B, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.
Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544.
Ling J, Kang Y, Zhao R, Xia Q, Lee D-F, Chang Z, et al. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105–20.
Schmid MC, Avraamides CJ, Foubert P, Shaked Y, Kang S, Kerbel RS, et al. Combined blockade of integrin-β1 plus cytokines SDF-1α or IL-1β potently inhibits tumor inflammation and growth. Cancer Res. 2011;71:6965–75.
Tjomsland V, Bojmar L, Sandström P, Bratthäll C, Messmer D, Spångeus A, et al. IL-1α expression in pancreatic ductal adenocarcinoma affects the tumor cell migration and is regulated by the p38MAPK signaling pathway. PLoS One. 2013;8:e70874.
Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 2019;9:1102–23.
Calon A, Espinet E, Palomo-Ponce S, Tauriello D, Iglesias M, Céspedes M, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–84.
Purcell JW, Tanlimco SG, Hickson JA, Fox M, Sho M, Durkin L, et al. LRRC15 is a novel mesenchymal protein and stromal target for antibody-drug conjugates. Cancer Res. 2018;78:4059–72.
Bausch-Fluck D, Hofmann A, Bock T, Frei AP, Cerciello F, Jacobs A, et al. A mass spectrometric-derived cell surface protein atlas. PLoS One. 2015;10:e0121314.
Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96.
Peng J, Sun B-F, Chen C-Y, Zhou J-Y, Chen Y-S, Chen H, et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 2019;29:725–38.
Maurer C, Holmstrom SR, He J, Laise P, Su T, Ahmed A, et al. Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes. Gut. 2019;68:1034.
Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell. 2017;171:1611–24.
Principe DR, Park A, Dorman MJ, Kumar S, Viswakarma N, Rubin J, et al. TGFβ blockade augments PD-1 inhibition to promote T-cell mediated regression of pancreatic cancer. Mol Cancer Ther. 2018;18:613–20.
Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza GS, Hoadley KA, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168.
Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Yang T-H, et al. The immune landscape of cancer. Immunity. 2018;48:812–30.
Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, et al. IL-1-induced JAK/STAT signaling is antagonized by TGF-beta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2018;9:282–301.
Koopmans T, Rinkevich Y. Mesothelial to mesenchyme transition as a major developmental and pathological player in trunk organs and their cavities. Commun Biology. 2018;1:170.
Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, et al. STAT3 Plays a Critical Role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 2011;71:5020–9.
Shien K, Papadimitrakopoulou VA, Ruder D, Behrens C, Shen L, Kalhor N, et al. JAK1/STAT3 activation through a proinflammatory cytokine pathway leads to resistance to molecularly targeted therapy in non–small cell lung cancer. Mol Cancer Ther. 2017;16:2234–45.
Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010;21:11–9.
Fletcher AL, Malhotra D, Acton SE, Lukacs-Kornek V, Bellemare-Pelletier A, Curry M, et al. Reproducible isolation of lymph node stromal cells reveals site-dependent differences in fibroblastic reticular cells. Front Immunol. 2011;2:35.
Morgan-Lappe S, Gish KC, Hickson JA, Purcell JW. Anti-huLRRC15 antibody drug conjugates and methods for their use.
van den Brink SC, Sage F, Vértesy Á, Spanjaard B, Peterson-Maduro J, Baron CS, et al. Single-cell sequencing reveals dissociation-induced gene expression in tissue subpopulations. Nat Methods. 2017;14:935–6.
Korsunsky I, Fan J, Slowikowski K, Zhang F, Wei K, Baglaenko Y, et al. Fast, sensitive, and accurate integration of single cell data with Harmony. Nat Methods. 2019.
Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM, et al. Comprehensive integration of single-cell data. Cell. 2019;177:1888–902.
Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539:309.
Herwig R, Hardt C, Lienhard M, Kamburov A. Analyzing and interpreting genome data at the network level with ConsensusPathDB. Nat Protoc. 2016;11:1889–907.
Huang D, Sherman BT, Tan Q, Collins JR, Alvord GW, Roayaei J, et al. The DAVID gene functional classification tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 2007;8:R183.
Sui SJ, Mortimer JR, Arenillas DJ, Brumm J, Walsh CJ, Kennedy BP, et al. oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes. Nucleic Acids Res. 2005;33:3154–64.
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B Methodol. 1995;57:289–300.
Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24.
Müller S, Cho A, Liu SJ, Lim DA, Diaz A. CONICS integrates scRNA-seq with DNA sequencing to map gene expression to tumor sub-clones. Bioinformatics. 2018;34:3217–9.
Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009;4:1184.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;W98–102.
Genetic effects on gene expression across human tissues. Nature. 2017;550:204.
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909–20.
Kowanetz M, Zou W, Gettinger SN, Koeppen H, Kockx M, Schmid P, et al. Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti–PD-L1). Proc Nl Acad Sci U S A. 2018;115:201802166.