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Gene expression analysis of tumors of TN and R clonal pairs in vivo

ABSTRACT: We previously had generated clonal mouse melanoma cell lines, where each clone was isolated in a RAFi/MEKi-resistant ( R ) or treatment-naïve ( TN ) state using the method CaTCH (clones: 2646TN, 2646R, 14559TN, 14559R, 13TN). We assessed the response to targeted therapy of these clones in in vivo experiments using RAFi/MEKi-treatments. Herey, we saw that, compared to the other treatment-naïve clones, 2646TN exhibited a strongly reduced response to targeted therapy. 2646TN displayed fast growth on drug after only five days, indicating an increased persistence and fast adaption to the treatment, while all other TN clones responded to the treatments and showed tumor regression for weeks before relapsing. To uncover intrinsic programs that might underlie th minimal response of 2646TN, we examined the transcriptome of untreated and short-term treated tumors comprising 2646TN, 2646R, 14559TN, 14559R, or 13TN clones . These clonal cell lines were injected subcutaneously into C57BL/6 mice and tumors were harvested either at tumor engraftment (untreated) or after 3 days of RAFi/MEKi treatment. Lviving cancer cells were sorted from the tumors by FACS and the markers CD45- and the cell line specific marker GFP+. Libraries were prepared using the Lexogen Quantseq 3' mRNA seq kit and sqeuencing was performed on an Illumina HiSeqV4 sequencer (single-read 50 read mode).

ORGANISM(S): Mus musculus

PROVIDER: GSE139236 | GEO | 2020/07/20

REPOSITORIES: GEO

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Project description:Lymph-node (LN) metastases predict for high recurrence rates in breast cancer patients. Eradication of micro-metastatic tumor cells is the primary goal of adjuvant systemic treatment. Decisions regarding systemic treatment depend largely on primary tumor characteristics rather than on characteristics of their LN metastases. However, it remains unclear to what extent LN metastases, having already metastasized locally, resemble their primary breast tumors and as such will be eradicated by the systemic therapy chosen. In this study we investigated the genetic differences between primary breast cancers and their paired LN metastases using array comparative genomic hybridization analyses on a high resolution 720K Nimblegen platform. Thus far, no metastasis-specific genomic aberrations have been identified. We hypothesized that this is due to low-resolution platforms and lack of stratification on breast cancer subtypes (specifically, triple-negative (TN) versus luminal). Furthermore, we speculated that as TN tumours are known to be more genetically unstable, their LN metastases would show an increase in random copy number aberrations (CNAs). Therefore, we studied 10 primary TN breast tumour–LN pairs and 10 luminal pairs and found that all LN metastases clustered nearest to their matched tumour except for two. These two were explained by poor hybridization quality and, interestingly, the presence of two histological components in one tumour. We found no significantly altered CNAs between pairs in the whole group, nor when subdivided over subtypes; neither did we find a CNA increase in LN metastases compared to primary tumours within the TN subgroup, suggesting most CNAs are functional and not random. Our findings suggest a strong clonal relationship between primary breast tumours and its LN metastases and support the use of the primary tumor characteristics to guide adjuvant systemic chemotherapy in breast cancer patients, since primary tumors and their subsequent LN metastases seem remarkably similar, at least prior to treatment. The experiment contains 27 paired primary breast cancer samples with their lymph node metastases, analysed on a 135K whole genome CGH array

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Gene expression analysis of tumors of TN and R clonal pairs in vivo

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