Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts

Abstract

Preclinical models often fail to capture the diverse heterogeneity of human malignancies and as such lack clinical predictive power. Patient-derived tumor xenografts (PDX) have emerged as a powerful technology: capable of retaining the molecular heterogeneity of their originating sample. However, heterogeneity within a tumor is governed by both cell-autonomous (e.g., genetic and epigenetic heterogeneity) and non-cell-autonomous (e.g., stromal heterogeneity) drivers. Although PDXs can largely recapitulate the polygenomic architecture of human tumors, they do not fully account for heterogeneity in the tumor microenvironment. Hence, these models have substantial utility in basic and translational research in cancer biology; however, study of stromal or immune drivers of malignant progression may be limited. Similarly, PDX models offer the ability to conduct patient-specific in vivo and ex vivo drug screens, but stromal contributions to treatment responses may be under-represented. This review discusses the sources and consequences of intratumor heterogeneity and how these are recapitulated in the PDX model. Limitations of the current generation of PDXs are discussed and strategies to improve several aspects of the model with respect to preserving heterogeneity are proposed.

Figure 1

A shows a primary breast tumour including some sources of heterogeneity found in the native microenvironment. Reciprocal signalling pathways between tumour cells and tumour associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are highlighted. Extracellular matrix (ECM) is shown as collagen fibres with associated fibroblasts and macrophage/dendritic cells with T/B Lymphocytes are shown as part of the immune infiltrate, though other cell types (NK cells, myeloid derived suppressors etc.) have been omitted for simplicity. Panel B highlights patient matched fibroblasts and immune cells as possible candidates for co-engraftment in the next generation of PDX models. Current PDXs established in NSG mice lack an adaptive immune system and may have impaired innate immune cell infiltrates and cytokine signalling due to defective IL-2 receptor (33). Cancer associated fibroblasts are known to contribute to treatment response, although murine fibroblasts are present in PDX models, it is unclear how faithfully these recapitulate their human counterparts (26). Panel C shows a PDX tumour in its native microenvironment. Questions over whether pro- and anti- tumour CAF/TAM signalling pathways are present to the same extent in PDX models as in the primary tumour are highlighted. Stromal and tissue architecture can have profound effects on transcriptional regulation but are often overlooked in the establishment of PDX models (25). To highlight potential differences in ECM organisation between the native microenvironment and that of the PDX, here the ECM is shown as highly organised collagen fibres with closely associated myofibroblasts.