Institut Curie, Immunity and Cancer, PSL University, INSERM U932, Paris, France.
Université Paris Cité, INSERM U932, Paris, France.
Nat Cell Biol. 2023 Dec;25(12):1736-1745. doi: 10.1038/s41556-023-01291-w. Epub 2023 Nov 30.
Myeloid cell infiltration of solid tumours generally associates with poor patient prognosis and disease severity. Therefore, understanding the regulation of myeloid cell differentiation during cancer is crucial to counteract their pro-tumourigenic role. Bone marrow (BM) haematopoiesis is a tightly regulated process for the production of all immune cells in accordance to tissue needs. Myeloid cells differentiate during haematopoiesis from multipotent haematopoietic stem and progenitor cells (HSPCs). HSPCs can sense inflammatory signals from the periphery during infections or inflammatory disorders. In these settings, HSPC expansion is associated with increased myeloid differentiation. During carcinogenesis, the elevation of haematopoietic growth factors supports the expansion and differentiation of committed myeloid progenitors. However, it is unclear whether cancer-related inflammation also triggers demand-adapted haematopoiesis at the level of multipotent HSPCs. In the BM, HSPCs reside within the haematopoietic niche which delivers HSC maintenance and differentiation cues. Mesenchymal stem cells (MSCs) are a major cellular component of the BM niche and contribute to HSC homeostasis. Modifications of MSCs in systemic disorders have been associated with HSC differentiation towards myeloid cells. It is unknown if MSCs are regulated in the context of solid tumours and if their myeloid supportive activity is impacted by cancer-induced systemic changes. Here, using unbiased transcriptomic analysis and in situ imaging of HSCs and the BM niche during breast cancer, we show that both HSCs and MSCs are transcriptionally and spatially modified. We demonstrate that breast tumour can distantly remodel the cellular cross-talks in the BM niche leading to increased myelopoiesis.
实体瘤中的髓系细胞浸润通常与患者预后不良和疾病严重程度相关。因此，了解癌症中髓系细胞分化的调控对于对抗其促肿瘤作用至关重要。骨髓（BM）造血是一个严格调控的过程，根据组织的需要产生所有免疫细胞。髓系细胞在造血过程中从多能造血干细胞和祖细胞（HSPCs）分化而来。HSPCs 可以在感染或炎症性疾病期间感知来自外周的炎症信号。在这些情况下，HSPC 的扩增与髓系分化的增加相关。在癌变过程中，造血生长因子的升高支持定向髓系祖细胞的扩增和分化。然而，尚不清楚癌症相关炎症是否也会触发多能 HSPC 水平上适应需求的造血。在 BM 中，HSPC 位于造血龛位内，该龛位提供 HSC 维持和分化线索。间充质干细胞（MSCs）是 BM 龛位的主要细胞成分，有助于 HSC 稳态。系统性疾病中 MSCs 的改变与 HSC 向髓系细胞分化有关。尚不清楚 MSCs 是否在实体瘤的背景下受到调节，以及它们的髓系支持活性是否受到癌症引起的系统性变化的影响。在这里，我们使用无偏转录组分析和乳腺癌期间 HSCs 和 BM 龛位的原位成像，显示 HSCs 和 MSCs 在转录和空间上均被修饰。我们证明乳腺癌可以远距离重塑 BM 龛位中的细胞串扰，导致骨髓过度生成。
