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derived cells within microengineered platforms that 2.1. Cellular orchestrators of dormancy within the
recapitulate physiological cues (e.g., shear stress and BMME
cytokine gradients), BMOCs enable unprecedented real- The BMME coordinates tumor dormancy through
time observation and systematic dissection of dormancy dynamic niche reprogramming, where specialized micro-
mechanisms. Their modular design allows precise regional endosteal, perivascular, and immune niches
9
reconstitution of key BMME components—such as switch between dormancy enforcement and reactivation
angiogenic niches with controlled hypoxia or neuronal initiation through cell crosstalk 13,14 (Figure 2). In the
interfaces—facilitating mechanistic studies of dormancy endosteal niche, osteoblast-derived growth/differentiation
induction and escape that are difficult or impossible in factor 10 and transforming growth factor (TGF)-β2 bind
10
animal models. This human-centric approach inherently to TGF-β receptor III on DTCs, leading to the activation
enhances translational relevance. Coupled with high- of p38 mitogen-activated protein kinase (MAPK).
throughput screening capabilities, BMOCs represent a This signaling cascade induces phosphorylation of the
powerful, emerging toolset. 11,12 retinoblastoma protein at N-terminal sites (S249/T252),
While BMOC applications in tumor dormancy research thereby enforcing G0/G1 cell-cycle arrest and establishing
15
are nascent, their potential to decipher the spatiotemporal dormancy in DTCs. The perivascular niche utilizes
logic of dormancy and accelerate therapeutic discovery bone marrow mesenchymal stem cells (BMSCs) to guide
is substantial. This review introduces research progress DTC homing through the C–X–C motif chemokine 12
16,17
on cellular crosstalk within the BMME regulating tumor (CXCL12) gradient while inducing dormancy through
18-20
dormancy. It also discusses the conceptual framework growth arrest-specific protein 6 signaling and exosomal
microRNAs-mediated cell cycle inhibition.
Tumor-
21-23
and design principles of BMOC platforms for modeling derived TGF-β1 transforms BMSCs into cancer-associated
biological mechanisms of the BMME, ultimately aiming to fibroblasts, which secrete interleukin-6 (IL-6)/matrix
24
provide novel perspectives and methodologies for tumor metalloproteinase 9 (MMP-9) to degrade the extracellular
dormancy research and therapeutic interventions against matrix (ECM) and activate the integrin–focal adhesion
bone-metastatic tumors (Figure 1). kinase (FAK) reactivation pathway. When (neuron–
2. The BMME: A master regulator of tumor glial antigen 2-positive) NG2⁺ BMSCs co-migrate with
DTCs via N-cadherin adhesion, it promotes osteogenic
dormancy colonization. 25
While DTCs colonizing distant organs face the challenge The immune niche further complicates this balance.
of survival within foreign microenvironments, the bone Natural killer (NK) cells maintain dormancy through
marrow emerges as a critical sanctuary for metastatic interferon gamma (IFN-γ) surveillance, while myeloid-
26
cells. The BMME exerts deterministic control over derived suppressor cells and M2 macrophages disrupt
DTC fate through a functionally paradoxical duality: it immunity through programmed cell death 1 ligand 1/
enables efficient hematogenous dissemination yet actively IL-10, thereby fostering conditions for vascular escape. 27-29
enforces tumor dormancy through conserved regulatory The limitations of traditional models expose gaps in the
programs (predominantly characterized in animal study of multicellular dynamics. For example, the Transwell
models, necessitating verification in human contexts). co-culture system employed by Barcellos-de-Souza et al.,
30
This dual role positions the BMME as a central rheostat a system that only transmits signals through conditioned
balancing dormancy maintenance and reactivation. media, cannot simulate the bidirectional regulation of
Three interconnected mechanisms govern this regulation: TGF-β1 triggered by direct cell contact in vivo. Although
(i) cellular crosstalk between DTCs and resident BMME Zhang et al.’s mouse fracture model recapitulates the bone
25
populations (e.g., stromal cells and immune cells); remodeling process, it is limited by the resolution of in
(ii) molecular signaling cascades enforcing cell cycle arrest vivo imaging and cannot capture the real-time migratory
and metabolic adaptation; and (iii) niche remodeling interactions between NG2⁺ BMSCs and DTCs. In addition,
events triggering dormancy escape. Collectively, hypoxic the different production ratios and degradation rates of
gradients, cytokine networks, and mechanochemical cues cytokines among species pose significant difficulties for
within the BMME establish a dynamic equilibrium where cross-species studies. In summary, the cellular orchestrators
dormant DTCs persist in quiescence while retaining in the BMME provide a foundational framework for
reactivation potential. Decrypting this regulatory logic tumor dormancy, but reliance on non-human models
requires systematic dissection of how BMME components limits translational insights. Future BMOC-based studies
spatiotemporally constrain DTC proliferation—a could address these gaps by incorporating human-derived
complexity challenging to recapitulate in conventional cells and standardized vascular components to validate
models. dormancy mechanisms.

Volume 1 Issue 3 (2025) 2 doi: 10.36922/OR025200017