Mouse models in the era of large human tumour sequencing studies

Abstract

Cancer is a complex disease in which cells progressively accumulate mutations disrupting their cellular processes. A fraction of these mutations drive tumourigenesis by affecting oncogenes or tumour suppressor genes, but many mutations are passengers with no clear contribution to tumour development. The advancement of DNA and RNA sequencing technologies has enabled in-depth analysis of thousands of human tumours from various tissues to perform systematic characterization of their (epi)genomes and transcriptomes in order to identify (epi)genetic changes associated with cancer. Combined with considerable progress in algorithmic development, this expansion in scale has resulted in the identification of many cancer-associated mutations, genes and pathways that are considered to be potential drivers of tumour development. However, it remains challenging to systematically identify drivers affected by complex genomic rearrangements and drivers residing in non-coding regions of the genome or in complex amplicons or deletions of copy-number driven tumours. Furthermore, functional characterization is challenging in the human context due to the lack of genetically tractable experimental model systems in which the effects of mutations can be studied in the context of their tumour microenvironment. In this respect, mouse models of human cancer provide unique opportunities for pinpointing novel driver genes and their detailed characterization. In this review, we provide an overview of approaches for complementing human studies with data from mouse models. We also discuss state-of-the-art technological developments for cancer gene discovery and validation in mice.

Current methods in translational cancer research

“…For a variety of reasons, simple subcutaneous xenograft mouse models, where human tumor cells grown on a plate are injected into a mouse, are not robust tools in investigating tumor evolution [55,57]. This is, in part, due to the source material.…”

“…As discussed, cancer cells grown on plates are unreliable predictors of mutational progression in tumors due to numerous additional mutations cell lines acquire from repeated propagation on artificial tissue culture plates [12,58]. Indeed, cancer cell lines tend to lose their heterogeneity and become more homogeneous with continued selection on cell culture media in the absence of tumor microenvironment and immune influences [57,59]. Orthotopically implanting human or mouse cancer cells into a mouse yields a more representative model of tumor development because the implanted tumor is placed in the organ environment similar to that from which it originally arose [55,57].…”

“…Indeed, cancer cell lines tend to lose their heterogeneity and become more homogeneous with continued selection on cell culture media in the absence of tumor microenvironment and immune influences [57,59]. Orthotopically implanting human or mouse cancer cells into a mouse yields a more representative model of tumor development because the implanted tumor is placed in the organ environment similar to that from which it originally arose [55,57]. In the case of some tumor types, such as breast cancer, the orthotopically implanted tumor fragments are more representative models of tumor development and tumor microenvironment [55,57].…”

“…Unfortunately, syngeneic mouse tumors have the disadvantage of a lower mutational load than comparable human tumors [57]. In general, mouse tumors are less heterogeneous than human tumors because of inter-species differences [9,64].…”

“…As will be discussed, newer methods including Cre/loxP gene silencing, viral vectors, or CRISPR/Cas9 gene editing have emerged that dramatically alter the time scale of producing GEMMs [70]. GEMMs can also be induced to develop spontaneous tumors upon exposure to environmental factors (i.e., carcinogens, radiation) which can induce single nucleotide changes in genes and recapitulate a patient's tumor [57,93,94].…”