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

Wu HJ, Temko D, Maliga M, Moreira A, Sei E, Conterno Minussi D, Dean J, Lee C, Xu Q, Hochart G, Jacobson C, Yapp C, Schapiro D, Sorger P, Seeley EH, Navin N, Downey RJ, and Michor F

Cell Genomics. 2022 Aug; 2(8): 100165. PMID: 35404441

Intratumor 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 >5000 regions, single cell copy number sequencing of ~2000 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 geographic diversification of intratumor heterogeneity.