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| Status |
Public on Feb 12, 2020 |
| Title |
Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
small cell lung cancer CTC derived xenograft single cell RNA-sequencing
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| Contributor(s) |
Xi Y, Stewart A |
| Citation |
Stewart CA, Gay CM, Xi Y et al. Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer. Nature Cancer 2020. doi:10.1038/s43018-019-0020-z
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| Submission date |
Oct 01, 2019 |
| Last update date |
Oct 26, 2020 |
| Contact name |
Yuanxin Xi |
| E-mail(s) |
xiyuanxin@yahoo.com
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| Phone |
530-220-2067
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| Organization name |
The University of Texas MD Anderson Cancer Center
|
| Department |
Bioinformatics and Computational Biology
|
| Street address |
1400 Pressler St
|
| City |
Houston |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (25)
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| This SubSeries is part of SuperSeries: |
| GSE138474 |
Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer |
|
| Relations |
| BioProject |
PRJNA575243 |
| SRA |
SRP223887 |
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