A G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy is uncovered, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity.
Abstract
Background
Cancer progression involves not only uncontrolled proliferation but also the strategic entry of tumour cells into reversible (quiescent) or irreversible (senescent) states of cell cycle arrest (G0). These states can give rise to rare persister-like cancer cells that survive hostile tumour microenvironment conditions, facilitating drug resistance, metastasis and disease relapse. Despite their importance, identifying and understanding the mechanisms regulating these cell populations remains challenging.
Methods
We leveraged single-cell and spatially profiled primary breast tumours to quantify G0 arrest and proliferation decisions in cancer cells, revealing molecular and spatial features associated with proliferation-G0 dynamics.
Results
We uncovered a G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity. Spatial analyses revealed distinct ecological niches: G0 cells inhabited protective niches with complement pathway activity proximal to CXCL10+ macrophages and myofibroblastic cancer-associated fibroblasts (CAFs), whereas proliferative zones were associated with CLEC9A+ dendritic cells and PERK signalling, with distinct drug sensitivities.
Conclusions
Our findings highlight key principles underpinning G0-proliferation dynamics and niche specialisation in breast cancer, offering novel insights into the spatial drivers of tumour heterogeneity and evolution.
Cancer recurrence remains a leading cause of mortality in patients with solid tumors. Early disseminated tumor cells (DTCs), which seed distant organs during the initial stage of tumor progression, are widely recognized as an important source of late metastatic relapse. Tumor cell dormancy, a reversible but prolonged non-proliferative state, enables DTCs to survive in metastatic tissues for years or even decades before re-entering the cell cycle and giving rise to overt metastases. Accumulating evidence indicates that dormancy is regulated by both cell-intrinsic mechanisms, such as epigenetic reprogramming and metabolic adaptation, and extrinsic cues from the tissue microenvironment. Among these extrinsic regulators, ageing has emerged as a critical determinant of DTC fate by profoundly remodeling tissue microenvironments through cellular senescence, chronic inflammation, extracellular matrix (ECM) remodeling, vascular dysfunction, stromal metabolic rewiring, and immune dysregulation. These ageing-associated alterations progressively erode dormancy-supportive niches, thereby leading to metastatic reactivation. In this Review, we summarize the molecular mechanisms governing tumor dormancy and discuss how ageing-associated microenvironmental remodeling contributes to the reactivation of dormant DTCs. We highlight the roles of the senescence-associated secretory phenotype (SASP), ECM remodeling, vascular deterioration, and organ-specific stromal ageing in regulating the maintenance and exit of tumor dormancy. We also discuss emerging translational opportunities, including dormancy-reinforcing therapies, senolytic strategies, liquid biopsy-based surveillance, and advanced experimental platforms such as single-cell and spatial technologies. Collectively, this Review provides a conceptual framework for understanding how ageing progressively modulates tumor dormancy and highlights potential strategies to prevent late metastatic recurrence.
Faliang Wu, Yitong Meng, M. Cao et al.· Ageing and Cancer Research &...· 0 citations
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 0 citations
Prostate cancer is a heterogeneous disease shaped by evolving cellular states within a spatially organized tumor ecosystem. Advances in single-cell RNA-sequencing, single-nucleus sequencing, and spatial transcriptomics have facilitated high-resolution dissection of epithelial lineage hierarchies, tumor-associated luminal states, and microenvironmental remodeling. These approaches have revealed that progression from androgen receptor-dependent adenocarcinoma to castration-resistant prostate cancer and the development of neuroendocrine phenotypes reflect lineage plasticity and epigenetic reprogramming rather than simple linear genetic progression. Single-cell studies have indicated that immunosuppressive niches, cancer-associated fibroblast heterogeneity, endothelial activation, and metabolic adaptation collectively contribute to therapeutic resistance. The integration of multi-omics data with spatial context has begun to redefine prostate cancer taxonomy based on cellular state composition and ecosystem architecture. In this review, we summarize recent discoveries from single-cell and spatial analyses, discuss their implications for biomarker development and treatment stratification, and outline ongoing technical challenges, including standardization, reproducibility, and clinical scalability. Overall, this review provides valuable insights for the development of a state-informed framework to understand prostate cancer progression and guide precision oncology strategies.
Ryuta Watanabe, T. Chu, N. Miura et al.· American journal of clinical...· 2 citations
The progression from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) critically determines patient outcomes, yet its mechanisms remain incompletely understood. Integrating single-cell RNA sequencing, spatial transcriptomics, and genomics across 28 patients with synchronous DCIS and IBC, we delineate the spatial-molecular hierarchy of this transition. Invasion is primarily driven by clonal expansion of pre-existing DCIS subclones, emphasizing transcriptional reprogramming and tumor microenvironment (TME) remodeling over acquisition of additional driver alterations. IBC cells exhibit pronounced epithelial-mesenchymal transition and metabolic reprogramming. We uncover dynamic TME remodeling at the invasive front, identifying key ligand–receptor interactions (e.g., PPIA-BSG, MDK-LRP1, CXCL12-CXCR4) facilitating basement membrane disruption, angiogenesis and immunosuppression. Deconvolution of basement membrane breach reveals four molecularly defined stages (NMFT1–NMFT4) with progressively worsening patient survival. This study establishes a unified spatial-molecular atlas of DCIS-IBC progression, highlighting clonal expansion, transcriptional plasticity and TME remodeling as key drivers of invasion. The progression from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is not fully understood yet. Here, the authors integrate single-cell RNA-seq, spatial transcriptomics, and genomics data from patients with synchronous DCIS and IBC; they find clonal expansion, transcriptional plasticity, and tumour microenvironment remodelling as key drivers of DCIS-IBC progression.
Di Wang, Qichen Dai, Jing Guo et al.· Nature Communications· 0 citations
Tumor budding (TB) is a pathological hallmark of malignant invasion at the invasive front of colorectal cancer (CRC) and provides a morphologic window into early dissemination. In the International Tumor Budding Consensus Conference (ITBCC) framework, buds are single tumor cells or clusters of up to four cells, graded by hotspot counting to support standardized evaluation. Evidence from histopathology, single-cell profiling, spatially resolved analyses, and functional models links TB to invasion-competent tumor states. TB often tracks partial epithelial-mesenchymal transition, with weakened cell-cell adhesion, E-cadherin loss, altered β-catenin localization, and activation of integrin signaling, cytoskeletal remodeling, and extracellular matrix (ECM) degradation while retaining epithelial features. Spatial/trajectory analyses suggest that budding-rich regions concentrate plastic, stem-like programs biased toward migration and stress tolerance and lie close to intravasation. The TB niche also shows immune and metabolic specialization, with constrained dendritic-cell maturation and antigen presentation, reduced or dysfunctional CD8+ T-cell and NK-cell activity, and enrichment of tumor-associated macrophages and other suppressive myeloid programs. Hypoxia-driven glycolysis, lactate-associated acidification, adenosine signaling, and myeloid lipid-metabolic reprogramming can further stabilize invasive phenotypes and raise the threshold for immune control. Digital pathology and AI-enabled whole-slide analysis can improve scoring consistency and add spatial readouts linking TB patterns to immune contexture and stromal organization. Collectively, TB marks an interface between invasive tumor biology and the local microenvironment with direct relevance for risk stratification and therapeutic tailoring in CRC.
Ting Wang, Huanhuan Fei, Xiaofang Liu et al.· Biochemical and Biophysical...· 0 citations
Breast cancer progression is critically shaped by the tumor microenvironment, yet models that preserve patient-specific microenvironmental complexity remain limited. In particular, how the non-cellular microenvironment regulates macrophage-cancer cell crosstalk and contributes to tumor aggressiveness remains poorly understood. Here, we establish a patient-derived scaffold (PDS) model derived from decellularized breast cancer tissues as a platform to interrogate these interactions. Growth of MDA-MB-231 and MCF-7 cancer cells in PDSs reshaped cytokine gene expression and secretory profiles, leading to transcriptional reprogramming of THP-1 monocytes. Additionally, THP-1 cells were able to infiltrate PDSs and adopted macrophage-like states characterized by increased expression of M2- and pluripotency-related genes, alongside reduced proliferation signatures. Strikingly, transcriptional analysis of THP-1 PDS cultures identified a subset of PDSs derived from estrogen receptor-negative, CD163high tumors that preferentially induced upregulation of gene programs associated with macrophage differentiation and immunoregulatory gene signatures. Secreted molecules from these THP-1 PDS cultures, in turn, enhanced epithelial-to-mesenchymal transition (EMT)-related and immune-associated gene expression in cancer cells, particularly in MDA-MB-231, revealing transcriptional crosstalk linked to aggressive tumor features. Together, our findings demonstrate that the non-cellular tumor microenvironment preserved in PDSs is sufficient to drive coordinated transcriptional programs in both macrophages and cancer cells. The strong concordance between PDS-induced responses and clinical tumor characteristics underscores the potential of PDS-based models to uncover patient-specific tumor microenvironment interactions and guide future strategies targeting macrophage-cancer cell crosstalk in breast cancer.
Göran Landberg, Mikaela Ståhlberg, E. Frisk et al.· Biomedicine & pharmacotherap...· 0 citations