Abstract
Cancer progression is a complex process that involves tumor growth at the primary site coupled with dissemination and outgrowth at distant sites also known as metastasis. Majority of the cancer-related deaths are due to metastasis 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 understanding the function of granulocytic myeloid cells, an abundant component of the peripheral blood and tumor microenvironment. Using multiple models of breast cancer metastasis, we have characterized two distinct subpopulations of CD11b+Ly6G+ granulocytic myeloid cells in peripheral blood by RNA sequencing and proteomic profiling. The first subpopulation is abundant early before any detectable metastasis. A second subpopulation is abundant late coinciding with systemic metastasis. We have identified a network of paracrine signals between carcinoma and CXCR2 expressing CD11b+Ly6G+ granulocytic cells that drive metastasis. We find that CXCL1/2 chemokines from metastatic cells attract CD11b+Ly6G+ granulocytic myeloid cells, which in turn produce survival factors called S100A8/9 that promotes metastatic progression. Pharmacological inhibition of the CXCR2 axis in combination with chemotherapeutic agents significantly reduces multi-organ metastasis. We envision that a delicate balance exists between different granulocytic populations that function as a determinant of metastatic progression.
Citation Format: Swarnali Acharyya. Granulocytic cells in metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA05. doi:10.1158/1538-7445.CHTME14-IA05
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