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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer [RNA-Seq]

ABSTRACT: The natural history of small cell lung cancer (SCLC) includes rapid evolution from exquisite chemosensitivity to insurmountable chemoresistance. The mechanisms underlying treatment-resistance in SCLC remain obscure due to scarcity of tissue samples following relapse. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) and its contribution to treatment resistance. To investigate this, we performed single-cell RNAseq analyses of chemo-sensitive and -resistant CDXs, as well as longitudinal analyses of CDXs and patient CTCs. We found increased ITH, heterogeneous expression of pathways known to be associated with resistance, and transcriptional diversity of either therapeutic targets or EMT genes between cellular subpopulations following treatment-resistance to either chemotherapy or targeted therapies (PARP or CHK inhibitors). Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse, with gene expression patterns similar to a CDX from the same patient. These data suggest that treatment-resistance in SCLC is characterized by the presence of coexisting subpopulations of tumor cells with heterogeneous gene expression leading to activation of multiple, concurrent resistance mechanisms. These findings emphasize the need for drug development efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize the depth and duration of initial responses and counteract the rapid increase in ITH and emergence of broad therapeutic resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138267 | GEO | 2020/02/12

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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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer [RNA-Seq]

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