TY - JOUR
T1 - Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma
AU - Wang, Ruiping
AU - Dang, Minghao
AU - Harada, Kazuto
AU - Han, Guangchun
AU - Wang, Fang
AU - Pool Pizzi, Melissa
AU - Zhao, Meina
AU - Tatlonghari, Ghia
AU - Zhang, Shaojun
AU - Hao, Dapeng
AU - Lu, Yang
AU - Zhao, Shuangtao
AU - Badgwell, Brian D.
AU - Blum Murphy, Mariela
AU - Shanbhag, Namita
AU - Estrella, Jeannelyn S.
AU - Roy-Chowdhuri, Sinchita
AU - Abdelhakeem, Ahmed Adel Fouad
AU - Wang, Yuanxin
AU - Peng, Guang
AU - Hanash, Samir
AU - Calin, George A.
AU - Song, Xingzhi
AU - Chu, Yanshuo
AU - Zhang, Jianhua
AU - Li, Mingyao
AU - Chen, Ken
AU - Lazar, Alexander J.
AU - Futreal, Andrew
AU - Song, Shumei
AU - Ajani, Jaffer A.
AU - Wang, Linghua
N1 - Funding Information:
This study was supported by the start-up research fund provided to L.W. by the UT MD Anderson Cancer Center (MDACC); the Andrew Sabin Family Fellowship Program to L.W. by the Andrew Sabin Family Foundation; the DOD grants no. CA150334 and no. CA160445 to J.A.A.; the DOD grants no. CA160433 and no. CA170906 to S.S.; and the generous support from the Caporella, Dallas, Sultan, Park, Smith, Frazier, Oaks, Vanstekelenberg, Planjery, McNeil, Hyland and Cantu families; as well as from the Schecter Private Foundation, the Rivercreek Foundation, the Kevin Fund, the Myer Fund, the Stupid Strong Foundation, the V. Foundation, the Dio Fund, the Milrod Fund and the MDACC multidisciplinary grant programs. This study was also supported by the NIH grant no. 1S10OD024977-01 Award to the Advanced Technology Genomics Core (ATGC) and the Core grant no. CA016672 (ATGC). We thank E. J. Thompson and D. P. Pollock from the ATGC for their excellent technical assistance. We thank all of the patients who participated in this study.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/1
Y1 - 2021/1
N2 - Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
AB - Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
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UR - http://www.scopus.com/inward/citedby.url?scp=85098785926&partnerID=8YFLogxK
U2 - 10.1038/s41591-020-1125-8
DO - 10.1038/s41591-020-1125-8
M3 - Article
C2 - 33398161
AN - SCOPUS:85098785926
SN - 1078-8956
VL - 27
SP - 141
EP - 151
JO - Nature medicine
JF - Nature medicine
IS - 1
ER -