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.

Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges

“…Cancer is a very complex and heterogeneous disease that involves a broad range of mixed cells with distinct features. Tumor cells not only vary in morphology and phenotype but also, in genomes, transcriptomes, epigenomes and proteomes ( 1 ). Diversity among tumor cells termed heterogeneity can be observed between tumor cells within a tumor (intratumor heterogeneity).…”

Tyrosine Kinase Inhibitors Could Be Effective Against Non-small Cell Lung Cancer Brain Metastases Harboring Uncommon EGFR Mutations

“…A primary tumor is a mosaic of various clones that evolved from the original tumor cell(s) (27,28). Unlike cytotoxic chemotherapies that target all fast-growing cells, targeted treatments target specific cells within the tumor, raising the possibility of selecting resistant or unaffected clones, which can be responsible for relapse and metastasis (33,34). BMs show significant molecular divergence with the primary tumor and with extracranial metastases (30,31,(35)(36)(37)(38)(39).…”

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

“…To reduce the influence of murine stroma on the PDX model, co-engraftment of human mesenchymal stem cells or cancer-associated fibroblast cell lines in PDXs is explored. One promising approach is the isolation and co-engraftment of patient-derived fibroblasts [145].…”

“…However, this recommendation is not attributable to leukemia cell cultures where physiologically relevant concentration of the cells can be obtained in vitro for the research. Advances in cancer modeling were nicely reviewed in publications [25,30,89,145,177,189,196,197]. In our previous publication [198], 3D drug testing models with end-point viability-measuring methods were presented, including scaffold-based 3D culture systems, tissue slices, cellular spheroids, organoids, and organs-on-chips.…”