1: Chemokine networks regulate the balance of pro-and anti-tumor granulocytes that determine metastatic progression in breast cancer models
Cancer progression is a complex process that involves tumor growth at the primary site coupled with dissemination of cancer cells to vital organs and outgrowth of metastasis. Majority of the cancer-related deaths are due to metastatic outgrowth commonly occurring in the bone, lung, liver and brain. Although progress has been made in deciphering the process of tumor initiation and primary tumor growth, the molecular underpinnings and mechanisms of metastasis remain poorly understood. Given the role of the tumor microenvironment in cancer progression, there has been a growing interest in the function of myeloid cells, an abundant component of the peripheral blood and tumor microenvironment. Using multiple models of breast cancer metastasis, we uncovered a network of paracrine signals between carcinoma and bone marrow derived granulocytic myeloid cells that drive metastasis in breast cancer. We have recently identified two distinct subpopulations of CD11b + Ly6G + granulocytic myeloid cells by RNA sequencing, proteomic profiling and functional analysis with contrasting roles in metastasis. The first subpopulation is abundant early in the peripheral blood before any detectable metastasis. Adoptive transfer of the early population prior to tumor cell injection attenuates metastatic seeding. A second subpopulation is abundant late in the peripheral blood coinciding with systemic metastasis, which promotes metastatic colonization upon adoptive transfer. Additionally, we have identified specific signals and cues that entrain and recruit these two types of granulocytic cells in the tumor microenvironment. We find that CXCL1/2 chemokines from metastatic cells attract pro-tumor CD11b + Ly6G + granulocytic myeloid cells, which in turn produce survival factors called S100A8/9 that promotes metastatic progression. CCL2 on the other hand is involved in entraining the early granulocytic population to perform tumoricidal functions in early stages of metastasis. We envision that a delicate balance exists between the two granulocytic populations that function as a determinant of metastatic progression.