Intratumor Heterogeneity in Early Lung Adenocarcinoma

Abstract

Lung cancer is one of the deadliest diseases in the world and is the leading cause of cancer-related deaths. Among the histological types, adenocarcinoma is the most common, and it is characterized by a high degree of heterogeneity at many levels including clinical, behavioral, cellular and molecular. While most lung cancers are known for their aggressive behavior, up to 18.5% of lung cancers detected by CT screening are indolent and put patients at risk for overdiagnosis and overtreatment. The cellular and molecular underpinnings of tumor behavior remain largely unknown. In the recent years, the study of intratumor heterogeneity has become an attractive strategy to understand tumor progression. This review will summarize some of the current known determinants of lung adenocarcinoma behavior and discuss recent efforts to dissect its intratumor heterogeneity.

Keywords: clonal evolution; molecular alterations; single-cell; tumor behavior; tumor microenvironment.

Figure 1

Canonical molecular pathways altered in lung ADC (% from TCGA).

Figure 2

Branching process of tumor evolution in lung ADC. A tumor is depicted as a tree structure with the trunk representing ubiquitous (clonal) mutations present in all tumor regions (blue); shared branches representing heterogeneous (subclonal) mutations present in some tumor regions (purple), and private branches (also subclonal) representing unique mutations present in one tumor region only (green). The blue right triangle shows how as the chromosomal instability increases, the subclonal diversification is triggered. The bottom bar indicates that the smoking signature is associated with early events whereas the APOBEC signature is associated with late events.

Figure 3

Investigating intratumor heterogeneity and the TME with single cell approaches. A lung tumor resection is dissociated into single cell suspension which can be used in different applications. CyTOF uses metal-labeled antibodies to detect a limited number of proteins in the cells. Single cell RNA-Seq reveals the transcriptome of each individual cell. Both can be analyzed through computational strategies to dissect intratumor heterogeneity.