Abstract 3403: Conservation of colorectal cancer cell-intrisinc transcriptional traits in paired in vitro / in vivo cellular models
Authors: Isella Claudio , Petti Consalvo , Cancelliere Carlotta , Cantarella Daniela , Porporato Roberta , Trusolino Livio , Bertotti Andrea , Bardelli Alberto , Medico Enzo 
Published: August 2018

The best clinical and molecular criteria currently adopted in the diagnosis of colorectal cancer (CRC) often fail to predict the natural history of the disease, or to provide information regarding the molecular mechanisms inducing cancer onset and progression. To address these issues, molecular taxonomies based on transcriptional CRC subtypes have been developed; however, since the CRC transcriptome is heavily affected by mRNAs of stromal origin, these transcriptional traits are not specifically associated with cancer cell-intrisic features. To overcome this limitation, we recently employed gene expression profiles of CRC tissues specifically deprived of stromal transcripts to define “colorectal cancer cell-intrisinc subtypes” (CRIS). CRIS classification is not only bestowed with high prognositc and predictive value: it also conveys biological and molecular information on the subtypes, that may be tailored for specific therapies. To assess reliability of CRIS subtyping in preclinical CRC models, we designed a “XenoLine” platform, composed of 60 CRC cell lines representative of each CRIS class, grown in vitro and implanted in NOD-SCID mice to obtain xenograft tissues. After subcutaneous injection of 5 milion cells, xenografts were allowed to grow until they reached 2500 mm3 and were explanted. Engraftments were performed in duplicate and had a success rate around 85%. Further engraftments are ongoing. RNA-seq analysis was employed to compare in vivo- and in vitro-grown cells, and evaluate the stability of CRIS subtypes. The XenoLine RNA-seq profiles were in-silico microdissected, discriminating transcripts of epithelial cancer cell origin (human reads) from transcripts of stromal origin (mouse reads). Comparing paired in vitro / in vivo gene expression profiles, we observed that: 1) matched model pair correlation was systematically higher that random pair correlations; 2) for most genes, variation of expression across cells was consistent between in vitro and in vivo profiles; 3) CRIS classification was substantially maintained upon xenograft propagation. In conclusion, the molecular features distinguishing CRIS subtypes are resilient to major changes in cell growth conditions, such as changes in the microenvironment and acquisition of supporting stroma. The XenoLine platform was successfully established and will be further extended to better ascertain differences between in vitro- and in vivo- grown CRC cells of variable molecular makeup.

Citation Format: Claudio Isella, Consalvo Petti, Carlotta Cancelliere, Daniela Cantarella, Roberta Porporato, Livio Trusolino, Andrea Bertotti, Alberto Bardelli, Enzo Medico. Conservation of colorectal cancer cell-intrisinc transcriptional traits in paired in vitro / in vivo cellular models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3403.