Abstract
Cancer stem cells (CSCs) represent a small fraction of the total cancer cell population, yet they are thought to drive disease propagation, therapy resistance and relapse. Like healthy stem cells, CSCs possess the ability to self-renew and differentiate. These stemness phenotypes of CSCs rely on multiple molecular cues, including signaling pathways (for example, WNT, Notch and Hedgehog), cell surface molecules that interact with cellular niche components, and microenvironmental interactions with immune cells. Despite the importance of understanding CSC biology, our knowledge of how neighboring immune and tumor cell populations collectively shape CSC stemness is incomplete. Here, we provide a systems biology perspective on the crucial roles of cellular population identification and dissection of cell regulatory states. By reviewing state-of-the-art single-cell technologies, we show how innovative systems-based analysis enables a deeper understanding of the stemness of the tumor niche and the influence of intratumoral cancer cell and immune cell compositions. We also summarize strategies for refining CSC systems biology, and the potential role of this approach in the development of improved anticancer treatments. Because CSCs are amenable to cellular transitions, we envision how systems pharmacology can become a major engine for discovery of novel targets and drug candidates that can modulate state transitions for tumor cell reprogramming. Our aim is to provide deeper insights into cancer stemness from a systems perspective. We believe this approach has great potential to guide the development of more effective personalized cancer therapies that can prevent CSC-mediated relapse.
Highlights
In cancer, a gain of stemness can have profound implications on tumor aggressiveness, drug response and clinical outcome (Figure 1A)
Phenotypic plasticity of Cancer stem cells (CSCs) fuels adaptive phenotypes that contribute to tumor chemoresistance and poor clinical outcomes
A second layer of complexity arises from spatially distinct CSC niches
Summary
A gain of stemness can have profound implications on tumor aggressiveness, drug response and clinical outcome (Figure 1A). We provide a systems biology overview of how the immune cell niche, cellular contexts, and molecular or genetic perturbations contribute to stem cell-like properties of malignant cells. We start by describing the sources of tumor heterogeneity and defining the cellular niche as a dynamic spatial domain harboring cancer stem cells (CSCs). We elaborate on how this cellular niche is critical for communication between cell populations and move through
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