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Murine Pancreatic Tumor Cell Line TD2 Bears the Characteristic Pattern of Genetic Changes with Two Independently Amplified Gene Loci

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Murine Pancreatic Tumor Cell Line TD2 Bears the Characteristic Pattern of Genetic Changes with Two Independently Amplified Gene Loci Oncogene (2003) 22, 6802–6809 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Murine pancreatic tumor cell line TD2 bears the characteristic pattern of genetic changes with two independently amplified gene loci Bettina Schreiner1, Florian R Greten2,3, Dorotthe M Baur4, Alexander A Fingerle4, Ulrich Zechner4, Christian Bo¨ hm5, Michael Schmid5, Horst Hameister1 and Roland M Schmid3,4,* 1Department of Human Genetics, University of Ulm, D-89069 Ulm, Germany; 2Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, USA; 3Department of Internal Medicine II, Technical University of Munich, D-81675 Munich, Germany; 4Department of Internal Medicine I, University of Ulm, D-89069 Ulm, Germany; 5Institute of Human Genetics, University of Wu¨rzburg, D-97074 Wu¨rzburg, Germany TGFa/p53 þ /À transgenic mice represent a genetically that lead to final tumor development (Hruban et al., engineered mouse model for pancreatic adenocarcinoma. 2000; Bardeesy et al., 2001). To be able to investigate the The tumors develop a characteristic pattern of secondary different steps of genetic alterations occuring during genetic changes. From one of these tumors, the permanent cancer progression, a transgenic mouse tumor model cell line TD2 was established. Here, we describe in detail was established, in which TGFa is expressed under the the genetic changes by molecular–cytogenetic techniques. regulation of the elastase promoter. This ensures TGFa The original tumor-specific CGH profile has been retained overexpression restricted to pancreatic acinar cells unchanged. The most characteristic aberration pattern (Sandgren et al., 1990, 1991). It has already been shown bears chromosome 11. Egfr, localized on proximal that in this tumor model, the Ras/ERK pathway is chromosome 11, is amplified two to three times and leads constitutively active (Wagner et al., 2001). After a to an easily identifiable, stable marker chromosome with a latency period for more than 1 year, this leads to large amplification unit, which is present in each pancreatic tumor development. When crossed into a metaphase. The wild-type p53 gene on distal chromosome background of p53 þ /À heterozygous mice, the latency 11 is lost. The p16Ink4a locus on chromosome 4 is for tumor induction is reduced in a manner which turns hypermethylated. For c-Myc a 15-fold amplification, this tumor model feasible for laboratory investigation. present in a 1.65 Mb amplification unit, is detected on The tumors bear similar genetic changes, as were chromosome 15. Transition between presence in the form observed in human pancreatic cancer, which recom- of several double minutes, DMs, or a single homoge- mends this system as an in vivo model for pancreatic neously staining region, HSR, was observed for c-Myc. cancer (Wagner et al., 2001). Molecular–cytogenetic analysis of both amplification In this study, we describe the genomic changes in the units show that Egfr amplification and c-Myc amplifica- cell line TD2 originating from this genetically engineered tion represent two alternative modes by which genes get tumor model. A pattern of specific chromosomal aberra- amplified in tumor cells. The expression level of the tions that can be found in the original tumor tissue respective genes was proven by Northern blot analysis. (Schreiner et al., submitted) was detected. These changes The cell line TD2 represents a valuable in vitro model for include gain of proximal chromosome 11, encompassing pancreatic adenocarcinoma. epidermal growth factor receptor (Egfr), combined with Oncogene (2003) 22, 6802–6809. doi:10.1038/sj.onc.1206836 deletion of the distal part of the same chromosome, encompassing the wild-type p53 locus and hypermethy- Keywords: murine pancreatic tumor cell line; c-Myc lation of the p16Ink4a locus. Further recurrent genetic and Egfr amplification; p53 deletion; p16Ink4a hyper- changes were observed as gain of part of chromosome methylation 15, where c-Myc has been mapped, or – alternatively – ONCOGENOMICS loss of distal chromosome 14 including the Rb1 locus. Thus, the cell line TD2 and the mouse tumor progres- Introduction sion model represent powerful tools for future studies of pancreatic tumor growth in vitro and in vivo. Cancer of the pancreas is one of the most common cancer entities in human. Owing to the silent course of cancer development in the peritoneal cavity, this tumor Results gets diagnosed only at far advanced stages. This has hampered description of the cascade of genetic lesions Cytogenetic studies *Correspondence: RM Schmid, Chromosome analysis of the TD2 cell line was E-mail: [email protected] performed at passage 23 and 103. No striking differ- Received 11 April 2003; revised 2 June 2003; accepted 2 June 2003 ences were noticed. The chromosome number ranged c-Myc and Egfr amplification in the pancreatic cell line TD2 B Schreiner et al 6803 between 42 and 80. Of all the analysed metaphases, 87% confirmed. In the original tumor sample, an additional were hypertriploid to hypotetraploid, containing 65–77 loss of distal chromosome 11 including the p53 locus is chromosomes. In all metaphases, one large marker observed. In contrast to these findings, the CGH profile chromosome with distinct bands in the proximal half of distal MMU 11 of TD2 cells does not reach the cutoff and a varying number of several small marker chromo- level (Figure 2a). However, the loss of the wild-type p53 somes of uncertain origin were observed (Figure 1). allele on MMU 11 in TD2 cells was proven by independent PCR analysis (not shown). Analysis by spectral karyotypinq (SKY) Calibration of DNA copy changes by real-time PCR Spectral karyotyping (SKY) was performed at passage 20. One representative karyotype is shown in Figure 1, To define more exactly the length of the amplification consisting of an inverted DAPI-banded karyotype unit and the degree of amplification, calibration was together with the classified images in pseudocoloration. performed by real-time PCR (Figure 2b). For chromo- The chromosomal aberration pattern consists mostly of some 11, the following genes mapping to the proximal numerical aberrations. All chromosomes are represented 50 Mb of MMU 11 were tested: Egfr (9 cM; 16.8 Mb); three to four times except X and Y chromosomes, and reticuloendotheliosis oncogene, c-Rel (13 cM; 23.8 Mb); chromosome 17, which is present in five copies. Besides serine/threonine kinase 10, Stk10 (16 cM; 35.6 Mb); and several small marker chromosomes of varying number FMS-like tyrosine kinase 4, Flt4 (25 cM; 50.0 Mb). and undefined origin, one additional large marker Except Flt4, all analysed genes showed a relative chromosome is found in all metaphases. The proximal amplification of 2.2–3.0 times. Flt4, which maps at part of this marker chromosome is of chromosome 11 50 Mb, is not included in the amplification unit. There- origin and consists of three conspicuous dark-staining fore, the amplification unit extends at least 35.6 Mb but bands as already noticed in G-banded metaphases. The at most 49 Mb. distal part of the marker derives from chromosome 5. From MMU 15, the genes myelocytomatosis onco- Conventional banding and SKY analysis revealed this gene, c-Myc (32.0 cM; 62.4 Mb), adenylate cyclase 8, marker chromosome together with the small unidentifi- Adcy8 (37.5 cM; 65.1 Mb) and protein tyrosine kinase 2, able marker chromosomes as the only structurally Ptk2 (42.0 cM; 73.7 Mb) were chosen. The copy number rearranged chromosomes. of the genes Adcy8 and Ptk2 is not affected in this cell line, but for c-Myc 15–16 times amplification was CGH analysis detected (Figure 2b). To allow comparison of the cell line with the original Direct fluorescence in situ hybridization (FISH) analysis tumor sample, CGH analysis was performed with DNA with gene-specific probes extracted from the cell line at passage 25. Though the mean chromosome number indicates a highly aberrant Real-time PCR and CGH verified the amplification of karyotype, only two gains which surpassed the cutoff the c-Myc locus, although this has not been observed by level of 1.25 are detected (Figure 2a). Almost the whole conventional cytogenetic and SKY analysis (Figure 1). chromosome 17 and the proximal part of chromosome To detect the localization of the amplified c-Myc gene, 11 are amplified. For MMU 15, a very specific CGH fluorescence in situ hybridization (FISH) with c-Myc- profile is noticed with gain of chromosomal material at specific BAC probes (RPCI23-235H07, RPCI23-98D8, the beginning of the second half of the chromosome. RPCI23-55F11) was performed. Many strong signals Compared to the original tumor sample of that cell outside the chromosomes were observed (Figure 3a). line (not shown) the aberration pattern is widely These signals indicate the presence of double minutes Figure 1 Karyogram of a representative metaphase spread of cell line TD2 (passage 20) hybridized for SKY. Inverted DAPI stained and classified chromosomes in pseudocoloration are shown. Marker chromosomes are indicated by M Oncogene c-Myc and Egfr amplification in the pancreatic cell line TD2 B Schreiner et al 6804 (DMs) which are too small to get detected by conven- with HSRs it is too weak to get detected simultaneously tional DAPI banding. Another type of c-Myc amplifica- with the brilliant HSR signal. Therefore, a partial tion is observed by hybridization of the same BAC metaphase of TD2 is shown in Figure 3c. probes to metaphases prepared from higher passage The integration of the HSR does not occur on MMU cultures. Metaphases with a homogeneous staining 15 which harbors the endogenous c-Myc locus, but on region (HSR) of c-Myc DNA existed in parallel with another chromosome. By use of whole-chromosome metaphases, in which c-Myc was present as DMs painting probes, WCPs, the HSR-bearing chromosome (Figure 3b).
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