Introduction Progress in the development of effective cancer treatments is limited by the availability of tumour models that accurately reflect patient tumour with regards to histopathology, genomic landscape, and therapeutic response. To accomplish these needs, patient-derived tumour xenografts (PDX) were developed in recent years. Although they closely mirror structural and molecular features of the tumour of origin, PDXs still retain important restrictions related to maintenance costs and large-scale screening. To overcome this issue, we have established a novel platform of 2D cell lines (xeno-cell lines, XL) derived from PDXs of colorectal cancer (CRC) from which patient's germline gDNA was available. We have characterised XL-cells at multiple levels to assess their suitability as patient avatars to interrogate functional networks in colorectal cancer. Material and methods Exome and expression analysis were performed on the entire xeno-cell line collection. Biomarkers of response and resistance to anti-HER therapy have been annotated in cell lines and pharmacological analysis to validate drug targets has been accordingly completed. Results and discussions All XL-cells showed an epithelial-like morphology and phenotype, as also confirmed by EMT biomarker analysis. Genetic features (mutation and copy number profiles) were consistently preserved between PDXs and matched cell models, and expression analysis revealed XL-line collection as a significant representative of all CRC subtypes (CMS and CRIS subgroups). Whole exome and RNA-seq analyses allowed the identification of molecular biomarkers of response and resistance to targeted therapies, including EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XL-cells were confirmed in vivo in the corresponding PDX. Conclusion The XL-cell line platform represents a valuable preclinical tool for functional gene validation and proof of concept studies of novel therapeutics in colorectal cancer
