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Serial single-cell RNA sequencing unveils drug resistance and metastatic traits in stage IV breast cancer

ABSTRACT: Background: Drug resistance and metastasis are complex processes that remain poorly understood on the molecular level with single-cell resolution. We profiled the transcriptomic changes at the single-cell level associated with cancer cell progression, chemotherapy resistance, and metastasis in samples from a single de novo Stage IV breast cancer patient. Method: Pretreatment biopsy samples and posttreatment surgical specimens from the primary tumor and distant metastases were collected for single-cell RNA sequencing and subsequent cell clustering, copy number variation (CNV) estimation, transcription factor activity estimation, and pseudotime analyses. Results: CNV estimation analysis identified a small pretreatment cancer cell population that resisted chemotherapy and subsequently expanded. In the posttreatment primary tumors, new clones emerged, which we refer to as potential Metastatic Precursor Cells (MPCs), exhibiting the CNV profiles similar to metastatic cells. MPCs appeared to originate from hypoxic regions in the necrotic core of the tumor and exhibited expression profiles indicative of epithelial–mesenchymal transition. Comparison of MPCs to metastatic cancer cells also revealed dynamic changes in transcription factor activities and calcitonin pathway gene expressions. Conclusion: These findings demonstrate the utility of single-patient clinical sample analysis for clonal adaptations underlying tumor drug resistance, regrowth, and metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264205 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.

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Serial single-cell RNA sequencing unveils drug resistance and metastatic traits in stage IV breast cancer

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