Lineage factors and differentiation states in lung cancer progression

Abstract

Lung cancer encompasses a heterogeneous group of malignancies. Here we discuss how the remarkable diversity of major lung cancer subtypes is manifested in their transforming cell of origin, oncogenic dependencies, phenotypic plasticity, metastatic competence and response to therapy. More specifically, we review the increasing evidence that links this biological heterogeneity to the deregulation of cell lineage-specific pathways and the transcription factors that ultimately control them. As determinants of pulmonary epithelial differentiation, these poorly characterized transcriptional networks may underlie the etiology and biological progression of distinct lung cancers, while providing insight into innovative therapeutic strategies.

Figure 1.

Known and predicted influence of the cell of origin vs. oncogenic mutation in the formation of different lung cancer subtypes.

Figure 2.

Epigenetic and cellular context dictates the effect of lineage TFs in lung cancer. Given a specific cellular origin, lung cancer progression can be driven by repression of a lineage TF and its tumor suppressive gene targets. Conversely, amplification of a lineage TF may activate oncogenic genes following de novo TF complex formation at novel target promoters. The tumor suppressive and oncogenic activities may be adopted by the same TF in different epigenetic contexts. These contexts are defined by the overall abundance and availability of TFs and their partnering co-factors. TF thresholds may be dependent on cooperating mutations and different cellular origins (not depicted).

Figure 3.

Hypothetical mechanisms by which cell lineage plasticity and heterogeneity promote lung cancer metastasis. (A) Epithelial lineage positive malignant cells, such as NE cells in SCLC, constitute the majority of distant metastasis, but their dissemination is enhanced via non-cell autonomous signals from mesenchymal transitioned tumor cells in the primary tumor. (B) LUAD cells may disseminate via a classical EMT/MET model. (C) Alternatively, LUAD cells may undergo multiple switches in the expression of airway epithelial lineage specific markers that promote metastasis via cell autonomous mechanisms.