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Full Text (PDF) Published OnlineFirst September 18, 2018; DOI: 10.1158/2159-8290.CD-17-0987 RESEARCH ARTICLE Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin Dian Yang1,2,3, Sarah K. Denny2,4, Peyton G. Greenside5, Andrea C. Chaikovsky1,2,3, Jennifer J. Brady2, Youcef Ouadah1,6, Jeffrey M. Granja2,4, Nadine S. Jahchan2,3, Jing Shan Lim1,2,3, Shirley Kwok7, Christina S. Kong7, Anna S. Berghoff8,9,10, Anna Schmitt11, H. Christian Reinhardt11,12,13, Kwon-Sik Park14, Matthias Preusser9,10, Anshul Kundaje2,15, William J. Greenleaf2, Julien Sage1,2,3, and Monte M. Winslow1,2,7 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst September 18, 2018; DOI: 10.1158/2159-8290.CD-17-0987 ABSTRACT The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vul- nerabilities in advanced tumors. Here, using genetically defi ned mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplifi cation of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB- independent metastases arising from mature neuroendocrine cells. Our fi ndings underscore the impor- tance of the identity of cell type of origin in infl uencing tumor evolution and metastatic mechanisms. SIGNIFICANCE : We show that SCLC can arise from different cell types of origin, which profoundly infl u- ences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316–31. ©2018 AACR. See related commentary by Pozo et al., p. 1216. INTRODUCTION to acquire metastatic ability early in the course of tumor progres- sion, but emerging evidence suggests that this metastatic ability Most patients with cancer die from metastatic disease; how- is not inherent. Rather, genetic events such as upregulation of ever, many key aspects of metastatic progression remain poorly CXCR4 and NEUROD1 and/or amplifi cation ofNFIB are critical understood. In particular, the nature of the changes that drive for SCLC invasion and metastasis in at least a subset of patients metastasis and the potential impact of early events in tumori- ( 5–9 ). Recent data from genetically engineered mouse models genesis upon the direction of this evolution are largely unex- and human tumors have uncovered multiple levels of hetero- plored. A better understanding of these mechanisms could geneity in SCLC; however, how this heterogeneity pertains to help diagnose and treat patients more effectively ( 1, 2 ). metastatic progression is largely unexplored ( 10–19 ). Small cell lung cancer (SCLC) is one of the most metastatic SCLC is a neuroendocrine cancer; thus, it made sense when and lethal of all major cancer types ( 3, 4 ). SCLC is thought deletion of the key SCLC tumor suppressor genes Rb1 and Trp53 in pulmonary neuroendocrine cells uncovered these cells as one cell type of origin for SCLC in mouse models (refs. 1 Cancer Biology Program, Stanford University, Stanford, California. 2 Depart- ment of Genetics, Stanford University, Stanford, California . 3 Department of 20–22 ; reviewed in ref 4 ). Interestingly, although pulmonary Pediatrics, Stanford University, Stanford, California. 4 Biophysics Program, neuroendocrine cells are quite rare, induction of these same Stanford University, Stanford, California. 5 Program in Biomedical Informat- genetic alterations in the much more prevalent lung epithelial 6 ics, Stanford University, Stanford, California. Department of Biochemis- cell types expressing either Scgb1a1 (coding for CC10, a marker try, Stanford University, Stanford, California. 7 Department of Pathology, Stanford University, Stanford, California. 8 Institute of Neurology, Medical of club cells ) or Sftpc (coding for SPC, a marker of alveolar type II University of Vienna, Vienna, Austria. 9 Department of Medicine I, Medical cells) demonstrated that these cells have very little, if any, ability University of Vienna, Vienna, Austria. 10 Comprehensive Cancer Center CNS to serve as the cell of origin of SCLC ( 20, 21 ). Nonetheless, the Tumors Unit, Medical University of Vienna, Vienna, Austria. 11 Department lung epithelium contains many diverse cell types ( 23–25 ), and of Internal Medicine I, University Hospital of Cologne, Cologne, Germany. whether SCLC can be initiated from other cell types is unknown. 12 Cologne Excellence Cluster on Cellular Stress Response in Aging- Associated Diseases, University of Cologne, Cologne, Germany. 13 Center Here, through detailed molecular characterization of pri- for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. mary tumors and metastases, we identify two discrete paths 14 Department of Microbiology, Immunology, and Cancer Biology, University by which SCLC gains metastatic ability. Our data indicate 15 of Virginia School of Medicine, Charlottesville, Virginia. Department of that the same genomic alterations in different cell types give Computer Science, Stanford University, Stanford, California. rise to distinct subtypes of SCLC, and that the founding cell Note: Supplementary data for this article are available at Cancer Discovery type of origin can defi ne the trajectory of tumor progression. Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Authors: Monte M. Winslow, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B256 , Stanford, CA 94305. RESULTS Phone: 650-725-8696; Fax: 650 - 725 - 1534 ; E-mail: mwinslow@stanford. Mouse SCLC Initiated from Adult Neuroendocrine edu ; and Julien Sage, Stanford University School of Medicine, Mail code 5149, 265 Campus Drive, SIM1, Stanford, CA 94305. Phone: 650-724- Cells Gains Metastatic Ability without 9246; E-mail: [email protected] Upregulation of NFIB doi: 10.1158/2159-8290.CD-17-0987 To study the mechanisms underlying SCLC metastasis, we ini- © 2018 American Association for Cancer Research. tially used the well-characterized Rb1 fl o x / fl ox ;Trp53 fl o x / fl ox ; p130 fl o x / fl ox ; OCTOber 2018 CANCER DISCOVERY | 1317 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst September 18, 2018; DOI: 10.1158/2159-8290.CD-17-0987 RESEARCH ARTICLE Yang et al. A B Adeno Adeno CMV-Cre “CMV TKO” CGRP-Cre “CGRP TKO” Rb1flox/flox;Trp53 flox/flox;p130 flox/flox;R26 mTmG Rb1flox/flox;Trp53 flox/flox;p130 flox/flox;R26 mTmG C CMV-Cre D CGRP-Cre Primary tumor Liver metastasis Primary tumor Liver metastasis H&E H&E NFIB NFIB E F Score = 0 Score = 1 G 100 100 NFIB NFIB High score Medium 75 Low/neg 3 2 50 50 1 Score = 2 Score = 3 0 Percentage Percentage 25 human 0 SCLC NFIB 0 metastases Human SCLC metastases CMV-Cre CMV-Cre CGRP-Cre CGRP-Cre Primary Liver tumors met Figure 1. SCLC initiated from pulmonary neuroendocrine cells metastasizes without upregulating NFIB. A and B, Mouse models of SCLC. Rb1flox/flox; Trp53flox/flox;p130flox/flox;R26mTmG (TKO;mTmG) mice were transduced with either Adeno-CMV-Cre (“CMV TKO”) or Adeno-CGRP-Cre (“CGRP TKO”) to initiate SCLC. C and D, Representative hematoxylin and eosin (H&E) images of SCLC tumors from CMV TKO and CGRP TKO mice. Immunostaining for NFIB on pri- mary tumors and metastases is shown. Scale bars, 100 μm. E, Quantification of NFIB expression in primary tumors and liver metastases (met) from CMV TKO and CGRP TKO mice. F, Representative immunostaining for NFIB on human SCLC brain metastases. Expression score for NFIB is indicated. Scale bars, 100 μm. G, Quantification of NFIB expression in human SCLC metastases (including lymph node and brain metastases,N = 43). CGRP, calcitonin gene-related peptide. R26mTmG (TKO;mTmG) mouse model, in which we initiated Fig. 1A and B). These “CGRP TKO” mice developed many tumors via intratracheal delivery of an adenoviral vector fewer SCLCs than CMV TKO mice even when transduced with expressing Cre recombinase under the control of the broadly a 10- to 20-fold higher titer of Ad-CGRP-Cre (Supplementary expressed CMV promoter (Ad-CMV-Cre; refs. 7, 26). Thus, Fig. S1A). Nonetheless, both CMV TKO and CGRP TKO in this model, Trp53, Rb1, and p130 are inactivated in many mice developed SCLC and widespread metastatic disease with different cell types in the lung. We initially uncovered that in metastasis to multiple organs, including the lymph nodes this “CMV TKO” model, amplification of theNfib genomic and liver, 6 to 9 months after tumor initiation (Fig. 1A and D; locus and high expression of the NFIB transcription factor Supplementary Fig. S1B–S1H). Previous studies showed that in primary tumors is an important step during metastatic Ad-CMV-Cre and Ad-CGRP-Cre each can also initiate meta- progression (7). To further investigate SCLC metastatic pro- static SCLC in Rb1flox/flox;Trp53flox/flox mice, but again, 15-fold gression in a model in which the tumors arise from a defined more Ad-CGRP-Cre was used to initiate tumors (21, 28). cell type, we subsequently initiated tumors in TKO;mTmG mice As part of our characterization of primary tumors and with Ad-CGRP-Cre, which specifically directs Cre expression to metastases in CMV TKO and CGRP TKO mice, we performed mature, CGRP-expressing neuroendocrine cells (refs. 21, 22, 27; immunostaining for the prometastatic transcription factor 1318 | CANCER DISCOVERY OCTOBER 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research.
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