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
Author Information
- C Allison Stewart: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Carl M Gay: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Yuanxin Xi: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Santhosh Sivajothi: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- V Sivakamasundari: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Junya Fujimoto: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Mohan Bolisetty: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Patrice M Hartsfield: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Veerakumar Balasubramaniyan: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Milind D Chalishazar: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
- Cesar Moran: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Neda Kalhor: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- John Stewart: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Hai Tran: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Stephen G Swisher: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Jack A Roth: Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Jianjun Zhang: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- John de Groot: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Bonnie Glisson: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Trudy G Oliver: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA. ORCID
- John V Heymach: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Ignacio Wistuba: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Paul Robson: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. ORCID
- Jing Wang: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Lauren Averett Byers: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. lbyers@mdanderson.org. ORCID
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.
Humans
Lung Neoplasms
Neoplasm Recurrence, Local
Neoplastic Cells, Circulating
Single-Cell Analysis
Small Cell Lung Carcinoma
