Chimeric Tumor and Organ Transplantation Models

Mouse models of cancer development and progression provide a means to study tumor response in appropriate physiological contexts. However, mouse cancer progression and therapy models have traditionally suffered from many of the same problems as human clinical cancer research, including genetic heterogeneity and tumor-stage variability at the time of treatment. Additionally, most mouse models are not tractable genetic systems, making it difficult to recapitulate the diverse set of alterations that regularly occur during tumor development. The recent development of chimeric and tumor transplantation techniques address many of the limitations of conventional mouse genetics. These strategies allow for the somatic introduction of complex genetic alterations into a subset of cells in reconstituted tumors or organ systems. Moreover, these different approaches can be combined in such a way that tumors with multiple genotypes are rapidly produced. These matched pairs can be systemically introduced into recipient mice for the rapid ex vivo modification of preestablished malignancies allows the generation of "matched pairs" of tumors differing in a single defined lesion (i.e., aliquots of the same primary malignancy with and without a gene of interest). Thus, treatment studies can be performed (1) in the context of an otherwise normal organ system, (2) on tumors that are in their appropriate anatomical context, and (3) on tumors that are essentially identical besides the presence of defined experimentally introduced alterations. Here, we will introduce procedures for modifying both normal and transformed cells and their adaptation to study in vivo tumor biology.