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Niche microenvironments are essential for maintaining the phenotypic heterogeneity of primary cancer

ABSTRACT: Cancer is among the major causes of death worldwide, and treatment can be individualized according to a patient’s genotype. Primary cultures of cancer and normal cells provide more accurate information about tumour pathology compared with tumour-derived cell lines, and several methods are available for establishing primary cultures. However, these methods are inefficient, complicated and expensive. Here we describe a method to establish primary cultures of tumour cells, which we designate “isolated tumour-derived Cancer Cells” (iCCs) that retains the phenotypic heterogeneity of primary cancer cells in their in situ niche microenvironments. We used a custom filter, a Matrigel-coated plate, and modified embryonic stem cell (ESC) culture medium to isolate iCCs from tumour tissues of patients with colorectal cancer. All iCCs were viable, and approximately 90% of the cultures were passaged. The morphologies, genotypes and transcription profiles of iCCs were similar to those of their respective tumours of origin. Further, iCCs comprised a specific cell population that expressed Platelet-derived growth factor receptor (PDGFR), which contributes to forming the structure of the original ductal carcinoma. Our results demonstrate that ESC culture medium maintained the heterogeneity of ICCs by supporting the viability of PDGFR-expressing cells. The responses of iCCs to standard anti-cancer drugs differed compared with those of colon cancer cell lines. Moreover, the drug sensitivities of iCCs closely correlated with patients’ clinical outcomes. For example, a clinically significant finding was the reduction of the IC50 of crenolanib, an inhibitor of PDGFR signalling, for iCCs. Therefore, crenolanib may serve as an effective chemotherapeutic agent for managing colorectal cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99158 | GEO | 2017/05/23

SECONDARY ACCESSION(S): PRJNA387444

REPOSITORIES: GEO

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Project description:Human colorectal cancer (CRC) cell lines are a used widely-used to model system for investigation investigate of tumour biology, experimental therapytherapeutic and biomarkers discovery. However, to what extent these established CRC cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we analyzed 70 CRC cell lines were analysed for mutations using whole exome sequencing and DNA copy-number using by whole-exome sequencing and SNP microarray profilings, respectively. Presence of gGene expression was defined using RNA-Seq. Data from cellCell line datas were was compared to those that published from for primary CRCs published by in The the Cancer Genome Atlas Network. Notably, we found that The spectrum of exome mutations and DNA copy-number aberrations spectra in 70 CRC cell lines closely resembled those seen inat of primary colorectal tumours. Similarities included the presence of at least two hypermutation phenotypes, as defined by signatures of for defective DNA mismatch repair and DNA polymerase ? (POLE) proof-reading deficiency, and along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGF? and p53 pathways. In additionFurther, we documented mutations were enriched in genes involved in chromatin remodelling (ARID1A, CHD6, SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, TRRAP). Chromosomal instability was prevalent in non-hypermutated cases, with similar patterns of whole, partial and focal chromosomal aberrations and overlapping significant minimal regions ofchromosomal gains and losses. While paired cell lines derived from the same tumour were found to exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differenceslargely mainly reflected a pre-existing heterogeneity in the tumour cells heterogeneity. In conclusion, our results establish that human CRC lines are representative of the main subtypes of primary tumours at the genomic level, further validating underscoring their utility as tools for to investigating investigate CRC biology and drug responses. 69 colorectal cancer cell lines were analysed for DNA copy number profiles.

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Niche microenvironments are essential for maintaining the phenotypic heterogeneity of primary cancer

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