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Advances in genome and tissue engineering have spurred significant progress and opportunity for innovation in cancer modeling. Human induced pluripotent stem cells (iPSCs) are an established and powerful tool to study cellular processes in the context of disease-specific genetic backgrounds; however, their application to cancer has been limited by the resistance of many transformed cells to undergo successful reprogramming. Here, we review the status of human iPSC modeling of solid tumors in the context of genetic engineering, including how base and prime editing can be incorporated into "bottom-up" cancer modeling, a term we coined for iPSC-based cancer models using genetic engineering to induce transformation. This approach circumvents the need to reprogram cancer cells while allowing for dissection of the genetic mechanisms underlying transformation, progression, and metastasis with a high degree of precision and control. We also discuss the strengths and limitations of respective engineering approaches and outline experimental considerations for establishing future models.

Transposable elements are DNA sequences with the ability to move from one genomic location to another. The movement of class II transposable elements has been functionally harnessed and separated into two distinct DNA transposon components: the terminal inverted repeat sequences that flank genetic cargo to be mobilized and a transposase enzyme capable of recognizing the terminal inverted repeat sequences and catalyzing the transposition reaction. In particular, the Sleeping Beauty (SB) system was the first successful demonstration of transposon-based gene transfer in vertebrate species. Over the years, several improvements have been made to SB technology and more recent studies have demonstrated the versatility of the system for many applications including insertional mutagenesis, gene transfer, and transgenesis. These genetic engineering advances made available by SB both augment and advance large-scale efforts that have been directed toward identifying how genes and environmental factors influence human health in recent years. In the age of personalized medicine, the versatility of SB provides numerous genetic engineering avenues for answering novel questions in basic and applied research. This chapter discusses the use of SB-based insertional mutagenesis in mice for the efficient identification of candidate cancer genes across numerous types of cancers.