Abstract 5919: Identification of a novel molecular interaction, targeted by Metformin, between breast cancer and white adipose tissue progenitors
Authors: Reggiani Francesca , Labanca Valentina , Mancuso Patrizia , Manconi Andrea , Bertolini Francesco 
Published: July 2017

The white adipose tissue (WAT) contains a resident population of progenitors with mesenchymal- or endothelial-like phenotype, able to promote breast cancer (BC) progression (Orecchioni et al., 2013). We recently characterized a novel molecular axis underneath the interaction between BC and WAT progenitors, possibly explaining the acquisition of a cancer-associated phenotype by WAT progenitor cells and the establishment of a permissive tumor microenvironment. GM-CSF balance was identified to be the principal regulator of the transcriptional alteration occurring in WAT progenitors exposed to BC: GM-CSF, produced by BC cells, dramatically changed the secretion profile of progenitors, enhancing its own production through a positive regulatory loop and inducing the expression of several factors involved in inflammation (IL-1β), ECM remodeling and angiogenesis (MMP9). IL-1β was strongly down-regulated by GM-CSF neutralization in WAT progenitors in vitro and in preclinical models. Induction of IL-1β by GM-CSF was able, in turn, to up-regulate MMP9 in the same cells. The markedly increased expression of MMP9 was already observed in BC-associated WAT progenitors, being addressed to increased local and metastatic tumor growth in obese mice. GM-CSF production was significalntly enhanced in the presence of concomitant obesity in preclinical models of BC, both in orthotopic models (MMTV-neu/ErbB2; 4T1) and in spontaneous tumor-bearing mice (MMTV-PyMT). GM-CSF neutralization in several obese syngeneic models of BC significantly reduced immunosuppressive cells in tumors and in the surrounding WAT, including T-regs (CD4+CD25brightCD127low), Granulocytic myeloid-derived suppressor cells (G-MDSCs, CD11b+Ly6C-Ly6G+), tumor-associated macrophages (TAMs, F4/80+CD206+MCHIIlow) and tumor infiltrating lymphocytes (TILs, CD8+PD1+). Different BC types produce distinct amounts of GM-CSF: triple negative BC (TNBC) expressed higher levels compared to hormone receptors positive cells, correlating GM-CSF expression to higher tumor grade. In the context of targeting WAT-BC interaction, Metformin was able to impair tumor growth, metastasis and angiogenesis in preclinical models (Orecchioni et al., 2015) and affecting immune cells, including T-regs, TAMs and MDSCs. From our data, GM-CSF was identified to be a new target of Metformin in both BC and WAT progenitors, suggesting a novel inhibitory mechanism mediated by the drug. Metformin displayed the same efficacy in reducing BC growth, metastatic spread and immune system regulation, when compared to GM-CSF specific neutralization in obese syngeneic models. Taken together, these results indicate GM-CSF as a new molecular target of Metformin and support the role of this novel mechanism in BC progression. Ongoing studies also suggest that this pathway might be induced in WAT progenitors by other solid tumors, including non-Hodgkin’s B-lymphoma.

Citation Format: Francesca Reggiani, Valentina Labanca, Patrizia Mancuso, Andrea Manconi, Francesco Bertolini. Identification of a novel molecular interaction, targeted by Metformin, between breast cancer and white adipose tissue progenitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5919. doi:10.1158/1538-7445.AM2017-5919