Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer.
Document Type
Article
Publication Date
4-2020
Keywords
JGM
JAX Source
Nat Cancer 2020 Apr; 1:423-436
Volume
1
First Page
423
Last Page
436
ISSN
2662-1347
PMID
33521652
DOI
https://doi.org/10.1038/s43018-019-0020-z
Abstract
The natural history of small cell lung cancer (SCLC) includes rapid evolution from chemosensitivity to chemoresistance, although mechanisms underlying this evolution remain obscure due to scarcity of post-relapse tissue samples. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) via single-cell RNAseq of chemo-sensitive and -resistant CDXs and patient CTCs. We found globally increased ITH including heterogeneous expression of therapeutic targets and potential resistance pathways, such as EMT, between cellular subpopulations following treatment-resistance. Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse. These data suggest that treatment-resistance in SCLC is characterized by coexisting subpopulations of cells with heterogeneous gene expression leading to multiple, concurrent resistance mechanisms. These findings emphasize the need for clinical efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize initial responses and counteract the emergence of ITH and diverse resistance mechanisms.
Recommended Citation
Stewart C,
Gay C,
Xi Y,
Sivajothi S,
Sivakamasundari V,
Fujimoto J,
Bolisetty M,
Hartsfield P,
Balasubramaniyan V,
Chalishazar M,
Moran C,
Kalhor N,
Stewart J,
Tran H,
Swisher S,
Roth J,
Zhang J,
de Groot J,
Glisson B,
Oliver T,
Heymach J,
Wistuba I,
Robson P,
Wang J,
Byers L.
Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer. Nat Cancer 2020 Apr; 1:423-436