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

ABSTRACT: Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

PROVIDER: PRJNA576125 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10230454_1.fastq.gz	Fastqsanger.gz
	SRR10230454_2.fastq.gz	Fastqsanger.gz
	SRR10230455_1.fastq.gz	Fastqsanger.gz
	SRR10230455_2.fastq.gz	Fastqsanger.gz
	SRR10230456_1.fastq.gz	Fastqsanger.gz

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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]

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

| PRJNA575243 | ENA

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

Project description: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.

2020-02-12 | GSE138267 | GEO

Intratumoral heterogeneity of prostate cancers

Project description:Copy number analyses of regionally separated intratumoral biopsies of prostate cancers. Intratumoral heterogeneity (ITH) leads to regional biases of the mutational landscape in a single tumor and may influence the single biopsy-based clinical diagnosis and treatment decision. To evaluate the extent of ITH in unifocal prostate cancers (PCAs) that had not been sought, we analyzed multiple regional biopsies from three PCAs using DNA copy number analyses. DNA copy number showed ITH including regional biases in the presentation of a well-known driver of TMPRSS2-ERG fusion. Our analyses identified a substantial level of genetic ITH in unifocal PCAs at the genomic levels, which should be taken into account for the curation of biomarkers in the clinical setting. Four intratumoral biopsies were obtained per tumor for three prostate cancers. Radical prostatectomy tissue from three patients with prostate cancers were obtained. Board-certified pathologists reviewed the hematoxylin&eosin stained sections and identified tumor-rich regions (> 80% purity). We selected four different areas for biopsy that were at least 5mm apart and were comprised of the most common Gleason pattern (the most common histologic patterns with minimal histologic differences). Copy number profiling was performed using Agilent 180K platform according to the manufacturer's protocol.

2014-01-18 | E-GEOD-54185 | biostudies-arrayexpress

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-02-12 | GSE138474 | GEO

Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer

Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). 138 samples from patients with clear cell renal cell carcinoma, including biological replicates of nephrectomy samples. RNA extracted fresh frozen tissue samples.

2015-05-25 | E-GEOD-65615 | biostudies-arrayexpress

Intratumoral heterogeneity in cholangiocarcinoma

Project description:Intratumoral heterogeneity in cholangiocarcinoma

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Intratumoral heterogeneity of small cell lung cancer

Project description:Small cell lung cancer (SCLC) is a highly malignant tumor with extensive genomic alterations as detected by single-region sequencing. Yet, the intratumoral heterogeneity (ITH) of SCLC remains unknown. We subjected 120 tumor samples from 40 stage I-III SCLC to multi-regional whole-exome sequencing.

2021-07-02 | PRJEB45988 | EVA

Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer (CGH)

Project description:The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mRCC). To explore ITH in detail, multiple tumor samples were taken from the primary renal tumors of mRCC patients who were sunitinib treated (n=23) or untreated (n=23). ITH of pathological grade, DNA (using array-based comparative genomic hybridisation), RNA (Illumina Beadarray) and protein (reverse phase protein array) were evaluated. Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). Unsupervised and supervised analysis, for renal cancer driver, hypoxia and stromal gene signatures, was then performed. In untreated patient tumor samples, significant ITH occurred in chromosomal aberrations, RNA and protein expression, with clustering of DNA and RNA correlating for individual patients. In unsupervised analysis sunitinib therapy was not associated with increased ITH in DNA or RNA. However there was an increase in ITH for the driver mutation and hypoxia gene signatures (DNA and RNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and RNA changes to targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Together these findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes. The results do not support the hypothesis that resistant clones are selected and predominate after initiation of targeted therapy; instead it appears that an initial clonal diversification occurs, supporting the hypothesis of polyclonal drug resistance. 128 samples from patients with clear cell renal cell carcinoma, including biological replicates of nephrectomy samples. Source of samples includes both biopsy and nephrectomy. DNA extracted from FFPE and fresh frozen tissue samples.

2015-05-25 | E-GEOD-67818 | biostudies-arrayexpress

Intratumoral heterogeneity of colorectal cancers with distant metastases

Project description:Copy number analyses of regionally separated biopsies from primary and metastatic lesions of five colorectal cancers A total of 35 intratumoral biopsies were obtained from primary and metastatic lesions of five colorectal cancers. Board-certified pathologists reviewed the hematoxylin&eosin stained sections and identified tumor-rich regions (> 80% purity) to ensure minimal contamination of normal tissues. We selected two to six different areas for biopsy that were at least 5mm apart in primary and distant metastatic lesions from a same patient. Copy number profiling was performed using Agilent 180K platform according to the manufacturer's protocol. The genomic DNA obtained from the adjacent normal tissues were used as reference genomic DNA for the tumor DNA of the corresponding patients.

2014-06-16 | E-GEOD-58512 | biostudies-arrayexpress

Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity and Molecular Features in Breast Cancer

Project description:Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Its biological features, particularly its intratumoral heterogeneity, remain obscure. Moreover, mechanism of lymph node metastasis is unclear. To address this deficiency, we performed single-cell transcriptome profiling of DCIS, invasive ductal carcinoma (IDC) and lymph node metastasis. Single-cell transcriptome analysis revealed that breast cancer exhibits intratumoral heterogeneity at the transcriptional level, defining specific functions, and that DCIS has similar heterogeneity to IDC.

2022-08-02 | GSE195861 | GEO

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