Mutations in foregut SOX2<sup>+</sup> cells induce efficient proliferation via CXCR2 pathway

doi:10.1007/s13238-019-0630-3

Protein Cell

2019, Vol. 10

Issue (7) : 485-495 https://doi.org/10.1007/s13238-019-0630-3

RESEARCH ARTICLE

Mutations in foregut SOX2⁺ cells induce efficient proliferation via CXCR2 pathway

Tomoaki Hishida¹, Eric Vazquez-Ferrer¹, Yuriko Hishida-Nozaki¹, Ignacio Sancho-Martinez¹, Yuta Takahashi¹, Fumiyuki Hatanaka¹, Jun Wu¹, Alejandro Ocampo¹, Pradeep Reddy¹, Min-Zu Wu^1,², Laurie Gerken³, Reuben J. Shaw^3,⁴, Concepcion Rodriguez Esteban¹, Christopher Benner⁵, Hiroshi Nakagawa^6,⁷, Pedro Guillen Garcia⁸, Estrella Nuñez Delicado², Antoni Castells⁹, Josep M. Campistol⁹, Guang-Hui Liu^10,^11,^12,^13,¹⁴(

), Juan Carlos Izpisua Belmonte¹(

)

¹. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
². Universidad Catolica, San Antonio de Murcia, Campus de los Jeronimos 135, Guadalupe 30107, Spain
³. Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
⁴. Howard Hughes Medical Institute, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
⁵. Integrative Genomics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
⁶. Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
⁷. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
⁸. Department of Traumatology and Research Unit, Clinica CEMTRO, Av. Ventisquero de la Condesa, 42, Madrid 28035, Spain
⁹. Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona 08036, Spain
¹⁰. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
¹¹. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
¹². University of the Chinese Academy of Sciences, Beijing 100049, China
¹³. Insitute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
¹⁴. Beijing Institute for Brain Disorder, Beijing 100069, China

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Abstract

Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2⁺ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as Kras^G12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2⁺ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for the acquisition of an invasive potential, and Kras^G12D expression, but not p53 deletion, suffices for tumor formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.

Keywords Sox2 tumor CXCR2 stratified epithelia

Corresponding Author(s): Guang-Hui Liu,Juan Carlos Izpisua Belmonte

Issue Date: 25 July 2019

Cite this article:

Tomoaki Hishida,Eric Vazquez-Ferrer,Yuriko Hishida-Nozaki, et al. Mutations in foregut SOX2⁺ cells induce efficient proliferation via CXCR2 pathway[J]. Protein Cell, 2019, 10(7): 485-495.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-019-0630-3
https://academic.hep.com.cn/pac/EN/Y2019/V10/I7/485

1	JC Acosta, A O’Loghlen, A Banito, MV Guijarro, A Augert, S Raguz, M Fumagalli, M Da Costa , C Brown, N Popovet al. (2008) Chemokine signaling via the CXCR1 receptor reinforces senescence. Cell 133:1006–1018 https://doi.org/10.1016/j.cell.2008.03.038
2	JR Adams, K Xu, JC Liu, NM Agamez, AJ Loch, RG Wong, W Wang, KL Wright, TF Lane, E Zacksenhauset al. (2011) Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res 71:2706–2717 https://doi.org/10.1158/0008-5472.CAN-10-0738
3	CL Andoniadou, D Matsushima, SN Mousavy Gharavy, M Signore, AI Mackintosh, M Schaeffer, C Gaston-Massuet, P Mollard, TS Jacques, P Le Tissieret al. (2013) Sox2(+) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell 13:433–445 https://doi.org/10.1016/j.stem.2013.07.004
4	L Annovazzi, M Mellai, V Caldera, G Valente, D Schiffer (2011) SOX2 expression and amplification in gliomas and glioma cell lines. Cancer Genom Proteom 8:139–147
5	K Arnold, A Sarkar, MA Yram, JM Polo, R Bronson, S Sengupta, M Seandel, N Geijsen, K Hochedlinger (2011) Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9:317–329 https://doi.org/10.1016/j.stem.2011.09.001
6	N Barker, JH van Es, J Kuipers, P Kujala, M van den Born, M Cozijnsen, A Haegebarth, J Korving, H Begthel, PJ Peterset al. (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007 https://doi.org/10.1038/nature06196
7	AJ Bass, H Watanabe, CH Mermel, S Yu, S Perner, RG Verhaak, SY Kim, L Wardwell, P Tamayo, I Gat-Vikset al. (2009) SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41:1238–1242 https://doi.org/10.1038/ng.465
8	C Blanpain, BD Simons (2013) Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol 14:489–502 https://doi.org/10.1038/nrm3625
9	S Boumahdi, G Driessens, G Lapouge, S Rorive, D Nassar, M Le Mercier, B Delatte, A Caauwe, S Lenglez, E Nkusiet al. (2014) SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature 511:246–250 https://doi.org/10.1038/nature13305
10	M Collado, M Serrano (2006) The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer 6 (6):472–476 https://doi.org/10.1038/nrc1884
11	JP Coppe, CK Patil, F Rodier, Y Sun, DP Munoz, J Goldstein, PS Nelson, PY Desprez, J Campisi (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868 https://doi.org/10.1371/journal.pbio.0060301
12	LA Davidson, ES Callaway, E Kim, BR Weeks, Y-Y Fan, CD Allred, RS Chapkin (2015) Targeted deletion of p53 in Lgr5-expressing intestinal stem cells promotes colon tumorigenesis in a preclinical model of colitis-associated cancer. Cancer Res 75(24):5392–5397 https://doi.org/10.1158/0008-5472.CAN-15-1706
13	DP Doupe, MP Alcolea, A Roshan, G Zhang, AM Klein, BD Simons, PH Jones (2012) A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337:1091–1093 https://doi.org/10.1126/science.1218835
14	Q Du, W Yan, VH Burton, SM Hewitt, L Wang, N Hu, PR Taylor, MD Armani, S Mukherjee, MR Emmert-Bucket al. (2013) Validation of esophageal squamous cell carcinoma candidate genes from high-throughput transcriptomic studies. Am J Cancer Res 3:402–410
15	Y Feng, GT Bommer, J Zhao, M Green, E Sands, Y Zhai, K Brown, A Burberry, KR Cho, ER Fearon (2011) Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology 141(1003–1013):e1001–1010 https://doi.org/10.1053/j.gastro.2011.05.007
16	M Gereke, A Autengruber, L Grobe, A Jeron, D Bruder, S Stegemann-Koniszewski (2012) Flow cytometric isolation of primary murine type II alveolar epithelial cells for functional and molecular studies. J Vis Exp. https://doi.org/10.3791/4322
17	DJ Huels, OJ Sansom (2015) Stem vs non-stem cell origin of colorectal cancer. Br J Cancer 113:1–5 https://doi.org/10.1038/bjc.2015.214
18	EL Jackson, N Willis, K Mercer, RT Bronson, D Crowley, R Montoya, T Jacks, DA Tuveson (2001) Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15:3243–3248 https://doi.org/10.1101/gad.943001
19	J Jonkers, R Meuwissen, H van der Gulden, H Peterse, M van der Valk, A Berns (2001) Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 29:418–425 https://doi.org/10.1038/ng747
20	J Kalabis, K Oyama, T Okawa, H Nakagawa, CZ Michaylira, DB Stairs, JL Figueiredo, U Mahmood, JA Diehl, M Herlynet al. (2008) A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J Clin Invest 118:3860–3869 https://doi.org/10.1172/JCI35012
21	A Krtolica, S Parrinello, S Lockett, PY Desprez, J Campisi (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 98:12072–12077 https://doi.org/10.1073/pnas.211053698
22	T Kuilman, C Michaloglou, WJ Mooi, DS Peeper (2010) The essence of senescence. Genes Dev 24:2463–2479 https://doi.org/10.1101/gad.1971610
23	T Kuilman, C Michaloglou, LC Vredeveld, S Douma, R van Doorn, CJ Desmet, LA Aarden, WJ Mooi, DS Peeper (2008) Oncogeneinduced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031 https://doi.org/10.1016/j.cell.2008.03.039
24	M Lesina, SM Wormann, J Morton, KN Diakopoulos, O Korneeva, M Wimmer, H Einwachter, J Sperveslage, IE Demir, T Kehlet al. (2016) RelA regulates CXCL1/CXCR22-dependent oncogeneinduced senescence in murine Kras-driven pancreatic carcinogenesis. J Clin Invest 126:2919–2932 https://doi.org/10.1172/JCI86477
25	DC Lin, JJ Hao, Y Nagata, L Xu, L Shang, X Meng, Y Sato, Y Okuno, AM Varela, LW Dinget al. (2014) Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet 46:467–473 https://doi.org/10.1038/ng.2935
26	K Liu, M Jiang, Y Lu, H Chen, J Sun, S Wu, WY Ku, H Nakagawa, Y Kita, S Natsugoeet al. (2013) Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells. Cell Stem Cell 12:304–315 https://doi.org/10.1016/j.stem.2013.01.007
27	QW Liu, JH Fu, KJ Luo, HX Yang, JY Wang, Y Hu, H Yang, E Bella (2011) Identification of EGFR and KRAS mutations in Chinese patients with esophageal squamous cell carcinoma. Dis Esophagus 24:374–380 https://doi.org/10.1111/j.1442-2050.2010.01155.x
28	Y Lu, C Futtner, JR Rock, X Xu, W Whitworth, BL Hogan, MW Onaitis (2010) Evidence that SOX2 overexpression is oncogenic in the lung. PLoS ONE 5:e11022 https://doi.org/10.1371/journal.pone.0011022
29	X Mao, Y, Fujiwara A Chapdelaine, H Yang, SH Orkin (2001) Activation of EGFP expression by Cre-mediated excision in a new ROSA26 reporter mouse strain. Blood 97:324–326 https://doi.org/10.1182/blood.V97.1.324
30	S Marino, M, Vooijs H van Der Gulden, J Jonkers, A Berns (2000) Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev 14:994–1004
31	A Mukhopadhyay, KC Berrett, U Kc, PM Clair, SM Pop, SR Carr, BL Witt, TG Oliver (2014) Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep 8:40–49 https://doi.org/10.1016/j.celrep.2014.05.036
32	SC Pruitt, KJ Bailey, A Freeland (2007) Reduced Mcm2 expression results in severe stem/progenitor cell deficiency and cancer. Stem Cells 25:3121–3132 https://doi.org/10.1634/stemcells.2007-0483
33	J Que, X Luo, RJ Schwartz, BL Hogan (2009) Multiple roles for Sox2 in the developing and adult mouse trachea. Development 136:1899–1907 https://doi.org/10.1242/dev.034629
34	CM Rudin, S Durinck, EW Stawiski, JT Poirier, Z Modrusan, DS Shames, EA Bergbower, Y Guan, J Shin, J Guilloryet al. (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44:1111–1116 https://doi.org/10.1038/ng.2405
35	M Safran, WY Kim, AL Kung, JW Horner, RA DePinho, WG Jr Kaelin (2003) Mouse reporter strain for noninvasive bioluminescent imaging of cells that have undergone Cre-mediated recombination. Mol Imaging 2:297–302 https://doi.org/10.1162/153535003322750637
36	A Sanchez-Danes, E Hannezo, JC Larsimont, M Liagre, KK Youssef, BD Simons, C Blanpain (2016) Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536:298–303 https://doi.org/10.1038/nature19069
37	A Sarkar, AJ Huebner, R Sulahian, A Anselmo, X Xu, K Flattery, N Desai, C Sebastian, MA Yram, K Arnoldet al. (2016) Sox2 suppresses gastric tumorigenesis in mice. Cell Rep 16:1929–1941 https://doi.org/10.1016/j.celrep.2016.07.034
38	S Schwitalla, PK Ziegler, D Horst, V Becker, I Kerle, Y Begus-Nahrmann, A Lechel, KL Rudolph, R Langer, J Slotta-Huspeninaet al. (2013) Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors. Cancer Cell 23(1):93–106 https://doi.org/10.1016/j.ccr.2012.11.014
39	M Serrano, AW Lin, ME McCurrach, D Beach, SW Lowe (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602 https://doi.org/10.1016/S0092-8674(00)81902-9
40	H Shigaki, Y Baba, M Watanabe, K Miyake, A Murata, S Iwagami, T Ishimoto, M Iwatsuki, N Yoshida, H Baba (2013) KRAS and BRAF mutations in 203 esophageal squamous cell carcinomas: pyrosequencing technology and literature review. Ann Surg Oncol 20(Suppl 3):S485–491 https://doi.org/10.1245/s10434-012-2819-z
41	M Singh, A Lima, R Molina, P Hamilton, AC Clermont, V Devasthali, JD Thompson, JH Cheng, H Bou Reslan, CC Hoet al. (2010) Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol 28:585–593 https://doi.org/10.1038/nbt.1640
42	HJ Snippert, AG Schepers, JH van Es, BD Simons, H Clevers (2014) Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep 15:62–69 https://doi.org/10.1002/embr.201337799
43	Y Song, L Li, Y Ou, Z Gao, E Li, X Li, W Zhang, J Wang, L Xu, Y Zhouet al. (2014) Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509:91–95 https://doi.org/10.1038/nature13176
44	M Tong, KW Chan, JY Bao, KY Wong, JN Chen, PS Kwan, KH Tang, L Fu, YR Qin, S Loket al. (2012) Rab25 is a tumor suppressor gene with antiangiogenic and anti-invasive activities in esophageal squamous cell carcinoma. Cancer Res 72:6024–6035 https://doi.org/10.1158/0008-5472.CAN-12-1269
45	RJ Vanner, M Remke, M Gallo, HJ Selvadurai, F Coutinho, L Lee, M Kushida, R Head, S Morrissy, X Zhuet al. (2014) Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer Cell 26:33–47 https://doi.org/10.1016/j.ccr.2014.05.005
46	JE Visvader, GJ Lindeman (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10:717–728 https://doi.org/10.1016/j.stem.2012.05.007
47	B Wang, DT Hendricks, F Wamunyokoli, MI Parker (2006) A growthrelated oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer. Cancer Res 66:3071–3077 https://doi.org/10.1158/0008-5472.CAN-05-2871
48	JR White, JM Lee, PR Young, RP Hertzberg, AJ Jurewicz, MA Chaikin, K Widdowson, JJ Foley, LD Martin, DE Griswoldet al. (1998) Identification of a potent, selective non-peptide CXCR45 antagonist that inhibits interleukin-8-induced neutrophil migration. J Biol Chem 273:10095–10098 https://doi.org/10.1074/jbc.273.17.10095
49	L Zhu, D Finkelstein, C Gao, L Shi, Y Wang, D Lopez-Terrada, K Wang, S Utley, S Pounds, G Nealeet al. (2016) Multi-organ Mapping of Cancer Risk. Cell 166(1132–1146):e1137 https://doi.org/10.1016/j.cell.2016.07.045

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