Abstract 2367A: CSF1-dependent macrophage-stromal fibroblast interactions determine tumor stability

Abstract

Abstract Tissue homeostasis is dependent on specialized ‘accessory’ cell types, which support the primary physiologic function of tissue parenchymal ‘client’ cells by performing essential accessory functions. We propose that metazoan tissues can be reduced to a minimal unit of three accessory subsets—tissue-resident macrophages, stromal fibroblasts, and endothelial cells—whose function and tissue composition is mutually dependent on CSF1R, PDGFRα, or VEGFR2 signaling from the Type III/V RTK family via their cognate growth factor ligands MCSF/IL34, PDGFα/β, or VEGFα, respectively. While each subset-specific growth factor is known to be essential for survival, proliferation, and differentiation, it is unknown to what extent growth factor supply is regulated cell extrinsically to create a stable tissue, and how accessory cell composition adapts to changes in tissue demands. Less is known of how tumor stability is disrupted by attenuation of growth-factor dependent stroma-stroma cues between tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs), and angiogenic endothelial cells (ECs), although tumor-stromal interactions are increasingly recognized as hallmarks of the heterogeneous cancer ‘organ.’ We hypothesized that growth factor supply and demand is controlled locally and adaptively in response to sensing/reporting interactions between these accessory subsets. To test this hypothesis, we developed an in vitro model of stroma-stroma growth-factor interactions via co-culture of primary bone marrow-derived macrophages (BMDMs) and mouse embryonic fibroblasts (MEFs). Data from co-culture, conditioned media transfer and stimulation assays demonstrates a 2-loop negative feedback circuit where: 1) stromal fibroblasts upregulate CSF1, chemokine ligands and ECM components in response to soluble signals (PDGFβ, TGFβ, IL1α) produced by MCSF-starved macrophages, and 2) PDGFβ is repressed as stromal cell:macrophage ratio increases, suggesting that macrophages sense a stromal derived ‘density factor’ and repress production of growth factors for stroma fibroblasts. Furthermore, study of in vivo transplantable and spontaneous melanoma models of the minimal tissue unit, demonstrate that destabilizing the tumor equilibrium by genetic and pharmacologic ablation of tumor and subset-specific CSF1/CSR1R and other RTK signaling can decrease tumor volume, alter accessory subset (TAMs/CAFs/ECs) ratios, and attenuate subset transcription, in a manner predictable by homeostatic growth-factor control circuits. We present a novel framework for understanding how tissue—and tumor microenvironment—composition and function is regulated by adaptable local control loops between parenchyma and accessory subsets, and propose alternative mechanisms of targeting the tumor microenvironment to destabilize the tumor ‘organ.’ Citation Format: Jeremy B. Jacox, Ruslan Medzhitov. CSF1-dependent macrophage-stromal fibroblast interactions determine tumor stability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2367A. doi:10.1158/1538-7445.AM2015-2367A