Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells

Abstract

Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy.

Non–small cell lung cancer-derived exosomes promote proliferation, phagocytosis, and secretion of microglia via exosomal microRNA in the metastatic microenvironment

“…However, this view of dual-polarization is now regarded as an oversimplification. Polarization is a dynamic process, and many studies have instead focused on observing the functional diversity of TAMs [ 8 , 40 , 41 ] . In this study, we observed that microglia aggregated around the brain metastases in mouse models and NSCLC patients.…”

Lung endothelium instructs dormancy of susceptible metastatic tumour cells

“…Similar default programs could occur in other organs in which ECs comprise a major Wnt source and were reported previously in different contexts 9,11 . Moreover, primary tumour-instructed remodelling of the niche could change the default state [45][46][47][48][49] . Additionally, the data strongly suggest that metastatic TCs actively inflicted a niche-EC gene program that resembled primary tumour EC signatures 29,50 and that could fuel TC proliferation by altering the biophysical properties of the micro-niche.…”

Signatures of Breast Cancer Progression in the Blood: What Could Be Learned from Circulating Tumor Cell Transcriptomes

“…By tracking CTC transfer rates, the authors extrapolated half-life times in the circulation ranging from 40 to 260 s and intravasation rates between 60 and 107,000 CTCs/hour in several mouse models [ 84 ]. Another recent work showed that, compared to intravascularly injected tumor cells, disseminating tumor cells developed spontaneously are retained longer and at higher frequency, extravasate from the lung vasculature more quickly and have a greater chance of survival after extravasation [ 85 ], corroborating the involvement of other microenvironmental factors in dissemination, such as primary tumor-associated macrophages [ 85 , 86 ]. The importance of cancer cell–cell cooperation and tumor-associated microenvironment cells in CTC survival has been largely documented [ 87 ], firmly demonstrating that the formation of homotypic and heterotypic clusters in experimental models endows cancer cells with higher colonization ability and proliferation rate than single CTCs.…”