Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer

C Allison Stewart; Carl M Gay; Yuanxin Xi; Santhosh Sivajothi; V Sivakamasundari; Junya Fujimoto; Mohan Bolisetty; Patrice M Hartsfield; Veerakumar Balasubramaniyan; Milind D Chalishazar; Cesar Moran; Neda Kalhor; John Stewart; Hai Tran; Stephen G Swisher; Jack A Roth; Jianjun Zhang; John de Groot; Bonnie Glisson; Trudy G Oliver; John V Heymach; Ignacio Wistuba; Paul Robson; Jing Wang; Lauren Averett Byers

doi:10.1038/s43018-019-0020-z

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. doi: 10.1038/s43018-019-0020-z. Epub 2020 Feb 17.

Authors

C Allison Stewart^#¹, Carl M Gay^#¹, Yuanxin Xi^#², Santhosh Sivajothi³, V Sivakamasundari³, Junya Fujimoto⁴, Mohan Bolisetty³, Patrice M Hartsfield¹, Veerakumar Balasubramaniyan⁵, Milind D Chalishazar⁶, Cesar Moran⁷, Neda Kalhor⁷, John Stewart⁷, Hai Tran¹, Stephen G Swisher⁸, Jack A Roth⁸, Jianjun Zhang¹, John de Groot⁵, Bonnie Glisson¹, Trudy G Oliver⁶, John V Heymach¹, Ignacio Wistuba⁴, Paul Robson³, Jing Wang², Lauren Averett Byers⁹

Affiliations

¹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
⁴ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
⁷ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lbyers@mdanderson.org.

^# Contributed equally.

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.

Keywords: CDX; CTC; SCLC; intratumoral heterogeneity; single-cell RNAseq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Humans
Lung Neoplasms* / drug therapy
Neoplasm Recurrence, Local / drug therapy
Neoplastic Cells, Circulating* / metabolism
Single-Cell Analysis
Small Cell Lung Carcinoma* / drug therapy

Abstract

Publication types

MeSH terms

Grants and funding