Defining the factors that control differentiation of conventional monocytes into macrophages during early metastasis in the lung 9370

Abstract Description Conventional monocytes (cMonos) and their progeny, macrophages, support metastasis by priming pre-metastatic niches and aiding tumor colonization. While cMonos recruited to the metastatic lung differentiate into metastasis-associated macrophages (MAMs) that support tumor survival, the molecular mechanisms driving this process within the metastatic tumor microenvironment (mTME) remain unclear. Environmental signals are key to determining cMono lineage fate. My preliminary work shows that cMonos differentiating into MAMs in metastatic lungs exhibit a distinct surface proteomic signature compared to those in naive lungs, highlighting the mTME’s role in their differentiation. To investigate this further, I used high-throughput flow cytometry (Infinity Flow) to profile cMonos at different stages of differentiation, alongside a pilot scRNA-seq assay using Flex from 10x. This revealed heterogeneity within the MAM population, identifying four distinct clusters that suggest multiple differentiation pathways for cMonos. Thus, I hypothesize that the early metastatic niche provides distinct, temporally regulated signals that program cMonos to differentiate into diverse cell fates. To test this, I executed a comprehensive time-course scRNA-seq and CITE-seq assay. Using advanced cell differentiation trajectory analysis tools like Palantir and Mellon, I aim to identify rare transitional states of cMonos and the signaling pathways orchestrating their differentiation into heterogeneous fates. Funding Sources NIH/NCI F31 Award Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)