Role of Transcription Factor Atf3 in the Bone Marrow Microenvironment During Breast Cancer Development: A Response Marker or an Active Player of Tumourigenesis?

Perrone, Milena (2022). Role of Transcription Factor Atf3 in the Bone Marrow Microenvironment During Breast Cancer Development: A Response Marker or an Active Player of Tumourigenesis? PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00013f00

Abstract

Cancer is a systemic disease able to reprogram the bone marrow (BM) niche towards a pro-tumorigenic state.

The timing in which BM cells start to sense the development of distant tumours and the molecular players involved in cancer-adapted immune response are largely unknown. In this context, by using the MMTV-NeuT mammary carcinoma mouse model, we have recently described the BM hematopoietic and stromal changes that support the initial steps of mammary transformation and identified the Activating transcription factor 3 (Atf3) among the genes significantly up modulated during the transcriptional reprogramming of the BM hematopoietic niche, at both early and late stages of disease. Additionally, Atf3 expression in the BM perfectly correlated with the pathologic disease score.

These data supported the need to further investigate the role of Atf3 during the BM emergency haematopoiesis associated with tumour progression.

In order to identify in which specific BM cell populations Atf3 was more expressed, we checked ATF3 activation in different progenitor and mature immune cell subsets starting from early stages of mammary gland transformation and along tumour progression. Taking advantage of two mouse models of luminal breast cancer, we demonstrated, extending previous observations, that ATF3 induction during cancer progression is a multistep process characterized by its activation in two different subsets of BM myeloid cells.

At early time point we observed high ATF3 expression and nuclear localization in common myeloid progenitor cells (FcγR+) localized in proximity of the vascular niche. This feature was maintained at invasive stage of mammary transformation, when ATF3 became also expressed in mature monocyte/macrophage cells.

Of note, the nuclear localization of ATF3 was associated with the formation of myeloid progenitor clusters in the BM of tumour-bearing mice and its overexpression in progenitor cells drove the expansion and the differentiation of monocyte/macrophage cells. The role of ATF3 in monocyte/macrophage differentiation was supported by in vivo data showing a defective recruitment of circulating monocytes and a low number of tumour-associated macrophages in PyMT41c tumours transplanted into Atf3fl/flLySMCre+/- mice.

Further studies demonstrated that BM-mesenchymal stem cells (BM-MSCs) were the first sensors of peripheral tumours and that ATF3 induction in the BM hematopoietic niche was the consequence of the cross talk between tumour-primed BM-MSCs and hematopoietic stem cells (HSCs), which ultimately leads to a tumour-restricted release of Atf3+ cells into the circulation.

Specifically, tumour-educated BM-MSCs, through the release of IL-1β, an inflammatory cytokines that induce HSCs to differentiate towards myeloid progenitor cells, activated Atf3 expression in naïve HSCs and initiated a specific lineage commitment.

Indeed, in vivo inhibition of IL-1β at early stage of disease significantly decreased Atf3 activation in HSCs and reduced myeloid progenitor clustering, a necessary step towards the establishment of emergency haematopoiesis. Furthermore, the blocking of IL-1β when the tumour was well-established caused a down-regulation of Atf3 expression in both precursors and mature monocytes and, consequently, decreased myeloid cell expansion.

Overall, this project demonstrated that the biphasic induction of ATF3 in the BM is functionally associated with a key role during emergency haematopoiesis and myeloid cell expansion, also suggesting a possible therapeutic targets.

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