It is demonstrated that cancer stem cells are hyper-responsive to microenvironmental cues, which they sense and adapt to through YAP/TAZ signalling, thereby playing an essential role in breast cancer lung metastasis.
Abstract
Cancer stem cells (CSCs) drive metastasis and therapy resistance, yet their behaviour within the complex tumour microenvironment remains poorly understood. Here we use a fluorescent reporter that marks CSCs to show that CSCs and their more differentiated progeny display strikingly different population dynamics during metastatic lung colonization in breast cancer models. CSC expansion is rapidly curtailed early in colonization, suggesting a strong negative feedback mechanism acting selectively on this subpopulation. We showed that CSCs are exceptionally sensitive to local microenvironmental cues such as cell crowding and nutrient availability. They respond earlier and more extensively than their differentiated progeny, thereby coupling tumour growth to resource and space availability. Microenvironmental signals converge on the transcriptional regulatory complex YAP/TAZ/TEAD, with CSC sensitivity arising from elevated signal reception and greater chromatin accessibility at TEAD-regulated enhancers. Targeting upstream inputs to this pathway reversed chemotherapy-induced CSC enrichment in lung metastases, suggesting a potential therapeutic strategy. Using a dynamic fluorescent reporter, Tang et al. demonstrate that cancer stem cells are hyper-responsive to microenvironmental cues, which they sense and adapt to through YAP/TAZ signalling, thereby playing an essential role in breast cancer lung metastasis.
A comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance is provided and emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion are critically discussed.
Hayam Hamdy, Youzhou Li, Chen Li et al.· Molecular Biomedicine· 0 citations
This review consolidates emerging evidence that positions cell competition as a critical regulator of clonal dynamics within the breast cancer TME and identifies competitive cellular fitness as a central and targetable driver of therapeutic resistance and tumor recurrence in breast cancer.
Esha Pal, Sovan Chakraborty, A. Guha· Frontiers in Oncology· 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
Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.
Mehreen Ahmed, A. Al-haidari, S. Agarwal et al.· Signal Transduction and Targ...· 0 citations
A particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment is focused on, which may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.
Jingyu Tan, Tao Wen, Jian Liu et al.· Journal of Hematology & Onco...· 0 citations
A residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases are identified, providing insights into the development of micrometastasis-targeting regimens.
Yunfan Sun, Y. Zhong, Shang Liu et al.· Science· 0 citations