Abstract A24: Bone marrow hematopoietic adaptation as a sensor of early, pre-invasive, epithelial malignancy

Abstract

Abstract Tumor development and progression is in part dependent on the ability of bystander cells, mostly of bone marrow (BM) origin, to establish a pro-tumorigenic microenvironment. We hypothesized that signs of the cross-talk between elements of the tumor microenvironment and the BM can be identified in the very early phases of cancer development, being finalized to the instruction of a tumor-promoting hematopoiesis. By integrating in situ BM histopathological and immunophenotypical analyses with flow cytometry and gene expression profiling of hematopoietic populations in a spontaneous mouse model of breast carcinogenesis (MMTV/NeuT) we investigated the occurrence and quality of modifications in the hematopoietic and stromal BM components and their correlation with the pathological stage of the mammary lesions. At the invasive carcinoma stage, histophathology and immunophenotyping of the BM hematopoietic parenchyma revealed a clear-cut switch towards a preferential granulo-monocytic fate, which was paralleled by a significant contraction in B-cell lymphoid populations and associated with the remodeling of the BM mesenchymal niches. At this stage, gene expression profiling of BM cells identified a differential gene signature on unsupervised analyses that allowed distinguishing between transgenic and control mice on the basis of inflammatory and innate immune response programs. The investigation at earlier stages of cancer development of such modifications in BM microarchitecture, hematopoietic composition, and gene profile demonstrated that their induction was already detectable at the high-grade dysplasia/in situ cancer stage, which provided the first evidence of the BM acting as a very early sensor of peripheral transformation. We hypothesized that the variations of the BM transcriptional profile could be paralleled by a reprogramming of the miRNA circulating in the peripheral blood. To text this hypothesis, we profiled plasmatic miRNAs at late and early stages of tumor progression and found, already at early time points, differentially expressed miRNAs, which could potentially be used as early biomarkers of cancerogenesis. In conclusion, our data lay a first demonstration that BM hematopoietic adaptation to cancer is not confined to the engendering of a general immunosuppressive state associated with advanced cancers, rather it represents an early process co-evolving with malignant clone expansion. These results, besides casting light on the identification of potential new biomarkers for early cancer detection, offer a whole new prospect on investigating the significance of early cancer-adapted hematopoiesis. Citation Format: Claudia Chiodoni, Andrea Massimiliano Tomirotti, Tiziana Ada Renzi, Matteo Dugo, Valeria Cancila, Claudio Tripodo, Mario Paolo Colombo. Bone marrow hematopoietic adaptation as a sensor of early, pre-invasive, epithelial malignancy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A24.