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Full Text (PDF) Published OnlineFirst April 21, 2011; DOI: 10.1158/0008-5472.CAN-10-4563 Cancer Tumor and Stem Cell Biology Research Uncoupling Cancer Mutations Reveals Critical Timing of p53 Loss in Sarcomagenesis Nathan P. Young1, Denise Crowley1,2, and Tyler Jacks1,2 Abstract It is well accepted that cancer develops following the sequential accumulation of multiple alterations, but how the temporal order of events affects tumor initiation and/or progression remains largely unknown. Here, we describe a mouse model that allows for temporally distinct cancer mutations. By integrating a Flp-inducible allele of K-rasG12D with established methods for Cre-mediated p53 deletion, we were able to separately control the mutation of these commonly associated cancer genes in vitro and in vivo. We show that delaying p53 deletion relative to K-rasG12D activation reduced tumor burden in a mouse model of soft-tissue sarcoma, suggesting that p53 strongly inhibits very early steps of transformation in the muscle. Furthermore, using in vivo RNA interference, we implicate the p53 target gene p21 as a critical mediator in this process, highlighting cell- cycle arrest as an extremely potent tumor suppressor mechanism. Cancer Res; 71(11); 4040–7. Ó2011 AACR. Introduction Saccharomyces cerivisae–derived Flp-Frt, exist but have been used in a more limited fashion in mouse models (4, 5). By Tumorigenesis is a multistep process driven by the accu- combining different SSR systems within the same model, one mulation of both genetic and epigenetic alterations in onco- could achieve spatiotemporal control of distinct genetic genes and tumor suppressor genes (1). These individual events provided the recombinases are independently regu- changes occur in a sequential manner and are thought to lated. drive distinct steps in the progression of normal cells to full Through its ability to respond to various forms of cellular malignancy (2). Although it is generally believed that the stress by inducing cell-cycle arrest or apoptosis, p53 plays a actions of these mutations combine to effect full transforma- central role in tumor suppression (6). Despite being one of the tion, it remains unclear how the order of events impacts this most thoroughly studied tumor suppressor genes, rather little process. is known about the precise stage(s) of tumorigenesis at which Although genetically engineered mice have been instru- p53 exerts its functions. In many human cancers, such as those mental in modeling and experimentally validating various of the lung, colon, and pancreas, p53 alterations have been attributes of human cancer, most current models that utilize documented in more advanced stages of tumor development, multiple cancer-associated mutations are not designed to suggesting that p53 constrains progression of established carry out sequential mutagenesis. As a result, one cannot tumors (7–9). In contrast, the early onset of several cancer directly test the importance of mutation timing or order. For types in patients with Li–Fraumeni syndrome, who inherit a example, although the use of multiple alleles controlled by the germ line mutation in p53, argues for a potential role of this conditional Cre-LoxP site-specific recombinase (SSR) system tumor suppressor in inhibiting the early stages of transforma- allows for the introduction of several cancer relevant muta- tion in some cell types (10). Although these studies establish tions, these mutations occur simultaneously at the time that p53 mutation correlates with different stages of tumor of tumor initiation (3). Additional SSR modalities, such as development, whether these differences underlie specific tem- poral requirements for p53 loss in distinct tissues remains to be determined. Authors' Affiliations: 1Koch Institute for Integrative Cancer Research and In addition to mutational data from human tumors, numer- Department of Biology, and 2Howard Hughes Medical Institute, Massa- ous mouse models have documented broad tumor-suppres- chusetts Institute of Technology, Cambridge, Massachusetts sive roles for p53 in numerous contexts (11). Both germ line Note: Supplementary data for this article are available at Cancer Research mutant and Cre-LoxP conditional alleles of p53 have been Online (http://cancerres.aacrjournals.org/). used to promote tumor formation in multiple tissues. How- Current address for N.P. Young: Molecular and Cellular Biology Labora- ever, most of these studies have not been able to pinpoint a tory, The Salk Institute for Biological Studies, La Jolla, CA 92037. specific requirement for p53 mutation as a function of tumor Corresponding Author: Tyler Jacks, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 40 Ames St. 76-453, progression. Here we describe a system for sequentially Cambridge, MA 02139. Phone: 617-253-0263; Fax: 617-253-9863; E-mail: mutating the commonly associated cancer genes K-ras and [email protected] p53. By combining an Flp-inducible allele of oncogenic K-ras doi: 10.1158/0008-5472.CAN-10-4563 with an already well-established Cre-regulated p53 deletion Ó2011 American Association for Cancer Research. allele (12), we were able to separately regulate these 4040 Cancer Res; 71(11) June 1, 2011 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst April 21, 2011; DOI: 10.1158/0008-5472.CAN-10-4563 Sequential Mutagenesis of K-ras and p53 mutations, both in cells and in mice. We show, using this dual pgk-Cre) was provided by M. DuPage (Koch Institute for SSR strategy, a clear effect of p53-mediated tumor suppression Integrative Cancer Research, Massachusetts Institute of Tech- in the earliest stages of soft-tissue sarcoma (STS) formation. nology, Cambridge, MA). Target sequences for short hairpin RNA (shRNA) knockdown were identified and cloned as Materials and Methods previously described (17). shRNA sequences are provided in Supplementary Material. Mouse studies Information on the construction of the K-rasFSF-G12D target- Lentiviral production ing construct and mouse strain, as well as details on additional Lentivirus was produced as described previously (18). mouse strains used in this study, are found in Supplementary Material. Lung tumors were generated and processed as pre- Histology and immunohistochemistry viously described (13–15), substituting Ad-Flpo (University of Tissues were fixed in 10% formalin for 6 to 8 hours and Iowa, Gene Transfer Vector Core) for Ad-Cre. Intramuscular further processed for histology as previously described (13). viral infections were done as previously shown (16). For green For immunohistochemistry (IHC), paraffin-embedded sec- fluorescent protein (GFP) marking experiments, needles were tions were dewaxed, followed by antigen retrieval in 10 dipped in India Ink before injection to mark the needle track. mmol/L citrate buffer (pH 6.0) in a pressure cooker. Slides Tamoxifen (Sigma) was dissolved in corn oil at 10 mg/mL and were quenched in 3% hydrogen peroxide and washed in Tris- injected intraperitoneally (i.p.) every other day for 5 days where buffered saline containing 0.05% Tween 20 (TBST). After applicable. Once masses were visible on the legs, tumors were blocking in TBST/5% goat serum for 1 hour, the primary processed for histology and molecular analysis as described in antibody (rabbit mAb anti-GFP, #2956; Cell Signaling Tech- the following text. For mouse embryonic fibroblasts (MEF) nology) was diluted 1:100 in SignalStain Antibody diluent tumor experiments, 1.5 Â 106 cells were resuspended in 200 mL (#8112; Cell Signaling Technology) and incubated on slides of PBS and injected s.c. Mice were monitored every few days for overnight at 4C. Detection was carried out using a biotiny- tumor formation. Animal studies were approved by the Mas- lated goat anti-rabbit secondary antibody, followed by the sachusetts Institute of Technology Committee for Animal Care Vectastain ABC kit with diaminobenzadine (DAB; Vector and conducted in compliance with Animal Welfare Act Reg- Labs). Slides were counterstained with hematoxylin before ulations and other federal statutes relating to animals and coverslipping. experiments involving animals and adheres to the principles set forth in the 1996 National Research Council Guide for Care Results and Use of Laboratory Animals (institutional animal welfare assurance number A-3125-01). To create a model for sequential mutagenesis in vivo,we sought to combine Flp-Frt-mediated mutagenesis with already Cell culture available tools from Cre–LoxP systems. To this end, we first Primary MEFs of the indicated genotypes were isolated generated a Flp-recombinase–inducible allele of oncogenic from E13.5 embryos and propagated in Dulbecco's modified K-ras (K-rasFSF-G12D), following a very similar strategy used Eagle's medium supplemented with 10% IFS, 5 mmol/L glu- to construct the well-studied Cre-inducible K-rasLSL-G12D allele tamine, and 100 U/mL penicillin/100 ug/mL streptomycin. (ref. 19; Fig. 1A and B). To characterize the activity of this allele, þ Where applicable, 4-hydroxytamoxifen (Sigma) was added to we first generated MEFs from K-rasFSF-G12D/ embryos. Intro- the media at 100 nmol/L. Lentiviral infections were carried out duction of an engineered thermostable version of Flp (Flpe; by directly transferring viral supernatant. For adenovirus ref. 20) but not Cre led to removal of the stop cassette, as infection in vitro, Ad-Flpo was added to the media at a shown by PCR analysis (Fig. 1C). In addition, Flpe expression
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