Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRNAs.

Abstract

The presence of a growing tumor establishes a chronic state of inflammation that acts locally and systemically. Bone marrow responds to stress signals by expanding myeloid cells endowed with immunosuppressive functions, further fostering tumor growth and dissemination. How early in transformation the cross-talk with the bone marrow begins and becomes detectable in blood is unknown. Here, gene expression profiling of the bone marrow along disease progression in a spontaneous model of mammary carcinogenesis demonstrates that transcriptional modifications in the hematopoietic compartment occurred as early as preinvasive disease stages. The transcriptional profile showed downregulation of adaptive immunity and induction of programs related to innate immunity and response to danger signals triggered by activating transcription factor 3. Transcriptional reprogramming was paralleled by the expansion of myeloid populations at the expense of erythroid and B lymphoid fractions. Hematopoietic changes were associated with modifications of the bone marrow stromal architecture through relocalization and increased density in the interstitial area of Nestin⁺ mesenchymal cells expressing CXCL12 and myeloid cells expressing CXCL12 receptor CXCR4. These early events were concomitant with deregulation of circulating miRNAs, which were predicted regulators of transcripts downregulated in the bone marrow and involved in lymphoid differentiation and activation. These data provide a link between sensing of peripheral cancer initiation by the bone marrow and hematopoietic adaptation to distant noxia through transcriptional rewiring toward innate/inflammatory response programs. SIGNIFICANCE: The bone marrow senses distant tissue transformation at premalignant/preinvasive stages, suggesting that circulating messengers, intercepted in the blood, could serve as early diagnostic markers.