Sleeping Beauty Mouse Models of Cancer: Microenvironmental Influences on Cancer Genetics

Guimarães-Young, Amy; Feddersen, Charlotte R.; Dupuy, Adam J.

doi:10.3389/fonc.2019.00611

Cited by 5 publications

(5 citation statements)

References 183 publications

(266 reference statements)

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“…We previously showed that multiparous MMTV-Cre:Rb f/f mice develop diverse mammary tumors as well as microscopic lung lesions presumed to represent metastatic descendants from primary mammary tumors 38 . The MMTV-Cre:Rb f/f mice were crossed with an activatable SB11 transposase, knocked into the ROSA26 locus (R26 lsl_SB11 ), and two different transgenic transposon concatemers, T2/Onc3a and T2/Onc3b, containing 11 and 28 copies on chromosomes 9 and 12, respectively 19 , 40 , 41 . As local hoping within the same chromosome occurs at higher frequency than across chromosomes, usage of both transposon donor lines enables coverage of the entire genome by omitting local transpositions in the T2/Onc3a and T2/Onc3b screens.…”

Section: Resultsmentioning

confidence: 99%

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Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer

Jiang,

Ju,

Ali

et al. 2023

Nat Commun

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Metastatic breast-cancer is a major cause of death in women worldwide, yet the relationship between oncogenic drivers that promote metastatic versus primary cancer is still contentious. To elucidate this relationship in treatment-naive animals, we hereby describe mammary-specific transposon-mutagenesis screens in female mice together with loss-of-function Rb, which is frequently inactivated in breast-cancer. We report gene-centric common insertion-sites (gCIS) that are enriched in primary-tumors, in metastases or shared by both compartments. Shared-gCIS comprise a major MET-RAS network, whereas metastasis-gCIS form three additional hubs: Rho-signaling, Ubiquitination and RNA-processing. Pathway analysis of four clinical cohorts with paired primary-tumors and metastases reveals similar organization in human breast-cancer with subtype-specific shared-drivers (e.g. RB1-loss, TP53-loss, high MET, RAS, ER), primary-enriched (EGFR, TGFβ and STAT3) and metastasis-enriched (RHO, PI3K) oncogenic signaling. Inhibitors of RB1-deficiency or MET plus RHO-signaling cooperate to block cell migration and drive tumor cell-death. Thus, targeting shared- and metastasis- but not primary-enriched derivers offers a rational avenue to prevent metastatic breast-cancer.

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Section: Resultsmentioning

confidence: 99%

“…Corrected p -values < 0.05 were called significant. The spindle protein gene Sfi1 was identified in both primary and metastatic lesions; this gene is frequently observed in SB screens due to its high copy number in the genome 19 , and was omitted from the analysis.…”

Section: Methodsmentioning

confidence: 99%

Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer

Jiang,

Ju,

Ali

et al. 2023

Nat Commun

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“…Identifying the responsible insertions as a follow-up is fairly simple, as transposons contain known sequences that can be used for PCR-based amplification and identification of the genomic neighborhood following NGS-based mapping. In addition, this technique has been of special interest for cancer research, as it was and still is successfully being employed to discover cancer-causing driver mutations [76] since the conception of the first oncogenic SB transposons suitable for large-scale screens in 2005. [77,78] www.advancedsciencenews.com www.bioessays-journal.com…”

Section: Insertional Mutagenesis Screens To Discover Genes and Deciphmentioning

confidence: 99%

Latest Advances for the Sleeping Beauty Transposon System: 23 Years of Insomnia but Prettier than Ever

Amberger

Ivics

2020

BioEssays

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The Sleeping Beauty transposon system is a nonviral DNA transfer tool capable of efficiently mediating transposition-based, stable integration of DNA sequences of choice into eukaryotic genomes. Continuous refinements of the system, including the emergence of hyperactive transposase mutants and novel approaches in vectorology, greatly improve upon transposition efficiency rivaling viral-vector-based methods for stable gene insertion. Current developments, such as reversible transgenesis and proof-of-concept RNA-guided transposition, further expand on possible applications in the future. In addition, innate advantages such as lack of preferential integration into genes reduce insertional mutagenesis-related safety concerns while comparably low manufacturing costs enable widespread implementation. Accordingly, the system is recognized as a powerful and versatile tool for genetic engineering and is playing a central role in an ever-expanding number of gene and cell therapy clinical trials with the potential to become a key technology to meet the growing demand for advanced therapy medicinal products.

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“…So far, the SB transposon has been used to identify driver genes in multiple types of cancers, including breast cancer 5 , melanoma 6 , osteosarcoma 7 , liver cancer 8 , pancreatic cancer 9 , colorectal cancer 10 , nervous system cancer 11 and other tumors 2 . Further interrogation of the SB-tagged mutations could facilitate the identification of the sophisticated drivers that are responsible for several important aspects of cancer, including tumorigenesis, metastasis 12 , 13 , tumor microenvironment influences 14 , and in vivo drug resistance 15 .…”

Section: Introductionmentioning

confidence: 99%

SB Digestor: a tailored driver gene identification tool for dissecting heterogeneous Sleeping Beauty transposon-induced tumors

Zhang¹,

Wang²,

Lei³

et al. 2023

Int. J. Biol. Sci.

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Sleeping Beauty (SB) insertional mutagenesis has been widely used for genome-wide functional screening in mouse models of human cancers, however, intertumor heterogeneity can be a major obstacle in identifying common insertion sites (CISs). Although previous algorithms have been successful in defining some CISs, they also miss CISs in certa in situ ations. A major common characteristic of these previous methods is that they do not take tumor heterogeneity into account. However, intertumoral heterogeneity directly influences the sequence read number for different tumor samples and then affects CIS identification. To precisely detect and define cancer driver genes, we developed SB Digestor, a computational algorithm that overcomes biological heterogeneity to identify more potential driver genes. Specifically, we define the relationship between the sequenced read number and putative gene number to deduce the depth cutoff for each tumor, which can reduce tumor complexity and precisely reflect intertumoral heterogeneity. Using this new tool, we re-analyzed our previously published SB-based screening dataset and identified many additional potent drivers involved in Brca1-related tumorigenesis, including Arhgap42, Tcf12, and Fgfr2. SB Digestor not only greatly enhances our ability to identify and prioritize cancer drivers from SB tumors but also substantially deepens our understanding of the intrinsic genetic basis of cancer.

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Sleeping Beauty Mouse Models of Cancer: Microenvironmental Influences on Cancer Genetics

Cited by 5 publications

References 183 publications

Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer

Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer

Latest Advances for the Sleeping Beauty Transposon System: 23 Years of Insomnia but Prettier than Ever

SB Digestor: a tailored driver gene identification tool for dissecting heterogeneous Sleeping Beauty transposon-induced tumors

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