From Chemotherapy to Combined Targeted Therapeutics: In Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

Abstract

Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH) for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (micro)environment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D) cell cultures and patient-derived tumor xenografts (PDX) as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.

Keywords: PD3D cell culture; PDX models; cancer models; cancer stem cells; organoids; tumor evolution; tumor heterogeneity; tumor microenvironment.

FIGURE 1

Potential applications of PD3D cell cultures derived from multiregional cancer biopsies in therapy selection (“Reverse Clinical Engineering”). The illustration shows how 3D cell cultures derived from multiregional sampling or biopsies can potentially improve the design of targeted therapies in cancer patients.

FIGURE 2

In vitro co-culture models of tumor–microenvironment interaction. The cartoon shows the main in vitro 2D and 3D co-culture models used to study tumor–microenvironment crosstalk.