Nat. cancer can be leveraged to interrogate tumor heterogeneity and to help design better therapeutic strategies. oncogene (locus, as well as an enrichment in accessible sites for Nfib transcription factor binding in the metastases (Denny et al. 2016). Experiments in cell-based systems and mice showed that increased levels of Nfib are necessary and sufficient to promote metastasis (Denny et al. 2016, Semenova et al. 2016, Wu et al. 2016). In contrast, in a different mouse STAT6 model of SCLC in which tumors are specifically induced in neuroendocrine lung epithelial cells (instead of non-neuroendocrine cells, as in the previous study), we found that amplification was not a frequent mechanism of metastasis (Yang et al. 2018). In humans, a majority of metastases, but not all, express high levels of NFIB (Denny et al. 2016, Semenova et al. 2016, Wu et al. 2016, Yang et al. 2018), which suggests that different mouse models may model different paths to metastatic development in humans. Genomic studies of human SCLC suggest that the gene is not very frequently amplified (George et al. 2015), suggesting that the switch may more often be epigenetic in human tumors (rather than genetic amplification of the locus leading to higher levels of expression). Together, these data from mouse models conclusively determine that SCLC is Kaempferol-3-rutinoside not necessarily inherently metastatic and identify a molecular switch in more than half of SCLC cases that endows cells with increased metastatic potential. In this context, cellular transformation is not sufficient to endow cells with metastatic potential. These studies identify a new level of intratumoral heterogeneity between primary tumors and metastases in SCLC. In lung adenocarcinoma, similar to the SCLC models, not all mouse tumors initiated synchronously by the same activation of KrasG12D and loss of p53 become malignant and metastatic, indicative of heterogeneity in tumor progression. Genomic analyses in mouse Kaempferol-3-rutinoside and human tumors identified the transcription factor Nkx2C1 (also known as Ttf-1) as a suppressor of metastatic progression (Winslow et al. 2011). Kaempferol-3-rutinoside One mechanism by which Nkx2C1 suppresses tumor progression and metastasis is usually by repression of the chromatin regulator Hmga2, which is normally only expressed during embryogenesis and in the adult testes (Winslow et al. 2011). While the mechanisms leading to Nkx2C1 silencing during tumor progression are not fully elucidated, deletion of the locus is usually rare (Winslow et al. 2011), suggestive of epigenetic silencing mechanisms such as DNA methylation. Interestingly, the Nkx2C1 target Selenbp1 (selenium-binding protein 1) was shown to be both an important regulator of metastatic progression and a regulator of Nkx2C1 expression, in a positive feedback loop (Caswell et al. 2018). During lung adenocarcinoma progression, a switch in metastasis between short and long isoform expression of the invadopodia scaffold protein Tks5 provides another example of functional nongenetic heterogeneity during metastatic progression (Li et al. 2013). Further comparison between primary tumors and metastases in the same mouse model of lung adenocarcinoma driven by activation of KrasG12D and loss of p53 also identified the basic helix-loop-helix transcription factor Arntl2, which controls a prometastatic secretome (Brady et al. 2016). The mechanisms leading to Arntl2 induction during the metastatic process are still unclear but may be in some ways related to Nkx2C1 silencing (Brady et al. 2016). One of the targets of Arntl2 is the extracellular matrix-associated protein Smoc2, whose induction may help produce a microenvironment conducive to lung adenocarcinoma metastasis (Brady et al. 2016). A new tumor barcoding system in the same mouse model allowed the Winslow lab to distinguish nonmetastatic primary tumors from primary tumors that had formed macrometastases. RNA-seq comparing these two types of primary tumors as well as metastases helped identify Jak (Janus kinase)/Stat (signal transducer and activator of transcription) signaling as an important driver of metastatic progression downstream of the CD109 cell.