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Spatial intra-tumor heterogeneity is associated with survival of lung adenocarcinoma patients.

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Wu, Hua-Jun 
Maliga, Zoltan 
Moreira, Andre L 
Sei, Emi 


Intra-tumor heterogeneity (ITH) of human tumors is important for tumor progression, treatment response, and drug resistance. However, the spatial distribution of ITH remains incompletely understood. Here, we present spatial analysis of ITH in lung adenocarcinomas from 147 patients using multi-region mass spectrometry of >5,000 regions, single-cell copy number sequencing of ~2,000 single cells, and cyclic immunofluorescence of >10 million cells. We identified two distinct spatial patterns among tumors, termed clustered and random geographic diversification (GD). These patterns were observed in the same samples using both proteomic and genomic data. The random proteomic GD pattern, which is characterized by decreased cell adhesion and lower levels of tumor-interacting endothelial cells, was significantly associated with increased risk of recurrence or death in two independent patient cohorts. Our study presents comprehensive spatial mapping of ITH in lung adenocarcinoma and provides insights into the mechanisms and clinical consequences of GD.



32 Biomedical and Clinical Sciences, 3211 Oncology and Carcinogenesis, Human Genome, Genetics, Rare Diseases, Clinical Research, Lung, Cancer Genomics, Cancer, Lung Cancer, Precision Medicine, Biotechnology, Cancer

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Cell Genomics

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We would like to thank the Michor lab for helpful discussions and David Sewell for editing. We gratefully acknowledge support of the Harvard Ludwig Cancer Center, the Dana-Farber Cancer Institute Physical Sciences-Oncology Center (NIH/NCI U54CA193461) and the CPRIT Single Cell Genomics Center at MD Anderson (RP180684); P.K.S. and Z.M. are supported by NIH/NCI grant U54-CA225088 and R50-CA252138. D.S. is supported by SNF Early Postdoc Mobility Fellowship P2ZHP3_181475. NIH grant U54-HL127365 supported tissue imaging at the Neurobiology Imaging Facility at Harvard Medical School.