Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and 4% of NSCLC patients are reported to harbor mutations in BRAF, which encodes a serine/threonine kinase capable of activating the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. However, the role and effects of BRAF mutation in NSCLC or lung lineage cells are not fully understood. To mimic the naturally occurring BRAF V600E mutation in lung cancer, a BRAF V600E knock-in BEAS-2B cell model was established using CRISPR/Cas9. Although the BRAF V600E mutation alone was not sufficient to drive lung carcinogenesis, it induced remarkable changes in cellular migration capacity and tumorigenic potential. Proteomics analysis revealed significant changes in the proteins involved in the biological processes including epithelial–mesenchymal transition (EMT), extracellular matrix (ECM)–receptor interaction, cell adhesion, focal adhesion, and cell metabolism upon the BRAF V600E mutation. Untargeted metabolomics experiments revealed that amino acid metabolism, especially glycine, serine and threonine metabolism, was significantly modulated in BRAF V600E knock-in cells. In summary, this study provides a new isogenic cell model that allows us to systematically dissect the underlying molecular events involved in the transition of cellular states upon the introduction of the BRAF V600E mutation.