Page 113 - OR-1-3

reconstructs three functionally interdependent metastatic retain the genetic/phenotypic heterogeneity of parental
microenvironments within a unified chip architecture tumors. When coupled with BMOC platforms, this
97
(Figure 6E): (i) a biomimetic dormancy niche where integrated system enables dynamic, stage-resolved analysis
98
3D-printed bone matrices with MSCs replicate cortactin- of tumor–stroma interactions. For example, the feasibility
regulated tumor–stromal interactions governing of co-culturing PDOs with fibrotic matrices/immune cells
quiescence; (ii) a physiologically accurate perivascular in microfluidic chips has successfully established complex
99
niche featuring engineered H-type microchannels lined organotypic tumor microenvironments. To further
96
100
with endothelial cells to simulate bone-specific vascular enhance physiological relevance, Du et al. developed
dynamics; and (iii) a vicious cycle niche demonstrating vascularized PDO chips featuring stratified microvascular
osteoclast-mediated reactivation of dormant cells. Crucially, networks, demonstrating that metastatic cells drive
quantitative cortactin or invadopodia analysis validated the angiogenesis through Notch signaling, with vascular
platform’s capacity to track dormancy-escape dynamics, density positively correlating with clinical metastatic
revealing MSC/osteoclast crosstalk as a master regulator of potential—providing a novel strategy for metastasis risk
metastatic reawakening. By simultaneously capturing these assessment.
three PMN transition phases in a human-relevant system, Collectively, these technological gaps demand
this approach overcomes a fundamental limitation of prior resolution through next-generation BMOC platforms.
models. It establishes a novel framework for identifying Future designs must integrate three strategic directions:
therapeutic targets against dormancy escape mechanisms. longitudinal monitoring technologies for dormant cell
dynamics, a PDO–BMOC hybrid multidimensional
4.3. Engineering next-generation BMOC technique: modeling framework for clinical translation, and precision-
Precision blueprints for dormancy breakthroughs
engineered vascularized organoid microenvironments.
Although BMOC platforms have achieved groundbreaking Only through such systematic innovations can BMOC
advances in dormancy mechanism research, significant substantially bridge the discrepancy between in vitro
limitations persist in modeling the dynamic monitoring models and dormancy biology research.
and biological complexity of metastatic dormancy and
reactivation. The primary challenge lies in dormant 5. Limitations and future directions
cell visualization—current systems typically rely on cell Although BMOCs can be used to simulate some
morphology or dormancy-associated protein detection, characteristics of the BMME and study cell–cell/matrix
lacking real-time monitoring capabilities. This deficit in interactions under specific physiological and pathological
monitoring technology may oversimplify critical dynamic conditions, the complexity found in vivo cannot be fully
processes during dormancy–awakening transitions, such as replicated, such as medullary cavity structures, vascular
inflammatory bursts or hemodynamic fluctuations triggered network, and neuronal network. These factors may
by bone remodeling. Static or simplified flow regimens significantly affect the development of tumor dormancy,
in existing chips struggle to replicate such physiological but their effects and mechanisms cannot be investigated
variability, potentially masking key reactivation triggers because simulating them in organ chips is difficult.
(e.g., immune surveillance or hormonal signaling cascades). Crucially, the bone marrow exists in a state of hypoxia
Notably, Correia et al. leveraged lentiviral delivery of or low oxygen concentration, with significant oxygen
26
mVenus-p27K reporters (specifically labeling quiescent gradients across its niches. Vascular niches exhibit higher
−
tumor cells) to enable real-time microscopic tracking of oxygen levels, while endosteal niches are profoundly
dormant cells, offering a novel strategy to overcome this hypoxic. This critical parameter regulates hematopoietic
101
limitation. cell behavior, including potential effects on dormancy.
102
Cellular fidelity bottlenecks similarly constrain Its faithful representation within BMOCs is essential for
translational value. Despite significant interpatient achieving physiologically relevant models. While studies
64
heterogeneity in dormancy behaviors, most BMOC studies such as Chou et al. have explored manipulating oxygen
103
employ immortalized cell lines or engineered stem cells to study HSC behavior, and Houshmand et al. identified
rather than patient-derived primary cells. This reductionist the absence of hypoxia as a key limitation in niche
approach may compromise clinical relevance, leading to modeling, robust integration and control of physiological
misrepresentation of key dormancy-regulating pathways oxygen gradients in complex BMOCs remain a significant
(e.g., p38 MAPK-dependent cell cycle arrest) in artificial challenge.
co-culture systems. The integration of organoid technology The 3D printing technology has been used to effectively
with BMOC is driving the evolution of multidimensional construct complex microstructures and simulate
modeling systems: patient-derived organoids (PDOs) the 3D structure and cell arrangement of the tumor
generated from primary or metastatic lesions faithfully microenvironment. 73,95,104 However, other hematopoietic

Volume 1 Issue 3 (2025) 16 doi: 10.36922/OR025200017