Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer.
Journal Article (Journal Article)
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.
- Stewart, CA; Gay, CM; Xi, Y; Sivajothi, S; Sivakamasundari, V; Fujimoto, J; Bolisetty, M; Hartsfield, PM; Balasubramaniyan, V; Chalishazar, MD; Moran, C; Kalhor, N; Stewart, J; Tran, H; Swisher, SG; Roth, JA; Zhang, J; de Groot, J; Glisson, B; Oliver, TG; Heymach, JV; Wistuba, I; Robson, P; Wang, J; Byers, LA
- April 2020
Volume / Issue
- 1 /
Start / End Page
- 423 - 436
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)