GSE104264
Transcriptome determinants of lung seeding by mammary tumor cells
Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine; that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis. Overall design: The study objective was to compare the transcriptomes of two independent variants of 4T1 cells with altered capacity to colonize lungs: (1) genetically modified 4T1 with Myb oncogene overexpression (MYBup), (2) 4T1 cells selected in vivo for high efficiency in lung seeding (lung3). Myb overexpression reduces the capacity of 4T1 cells to seed in lungs in experimental setting and to produce overt pulmonary metastases in orthotopic setting, whereas in vivo passaging rendered cells with enhanced metastatic ability. We tested the hypothesis that c-Myb drives transcriptional program preventing lung colonization by breast cancer cells, which is blunted in highly metastatic cells. To identify components of the program, we performed RNAseq and searched for genes that are either down-regulated in MYBup (compared to mock-transfected) and up-regulated in lung3 (compared to wt) or vice versa. All samples (mock, MYBup, wt, and lung3) were analysed in triplicates.