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Cells
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The Role of Stem Cells and Circadian Clock in Cancer...
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The Role of Stem Cells and Circadian Clock in Cancer Immunotherapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 857

Special Issue Editor

Dr. Yool Lee

E-Mail Website
Guest Editor
Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA
Interests: circadian clock; circadian disruption; cancer stem cells; tumor-immune microenvironment; cancer chronotherapy

Special Issue Information

Dear Colleagues,

Recent advances in cancer research have highlighted the critical interplay between stem cells and the circadian clock in regulating immune responses and cancer progression. Stem cells, including neural stem cells (NSCs) and cancer stem cells (CSCs), play pivotal roles in tumor initiation, maintenance, and resistance to therapies in both brain and peripheral cancers. Meanwhile, the circadian clock, a cellular timekeeping mechanism governing daily physiological rhythms, also influences immune system function, tumor microenvironment, and therapeutic outcomes. Disruptions in circadian rhythms have been linked to increased cancer risk and impaired efficacy of immunotherapies, making it crucial to understand how circadian mechanisms intersect with stem cell biology in the context of cancer treatment.

This Special Issue will explore the regulatory role of the circadian clock in stem cell dynamics and its implications for cancer immunotherapy. Topics of interest include the identification and characterization of stem cell subpopulations with circadian-dependent behaviors; the influence of circadian timing on immune checkpoints, tumor-infiltrating lymphocytes and cancer vaccines; the development of strategies to target circadian mechanisms for enhanced immunotherapeutic efficacy; and in vivo models and culture systems that simulate the circadian environment for investigating cancer stem cell behavior.

Dr. Yool Lee
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • circadian clock
  • circadian disruption
  • neural stem cells
  • cancer stem cells
  • tumor–immune microenvironment
  • cancer chronotherapy

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Published Papers (1 paper)

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Research

23 pages, 5019 KiB  
Article
Core Molecular Clock Factors Regulate Osteosarcoma Stem Cell Survival and Behavior via CSC/EMT Pathways and Lipid Droplet Biogenesis
by Sukanya Bhoumik and Yool Lee
Cells 2025, 14(7), 517; https://doi.org/10.3390/cells14070517 - 31 Mar 2025
Viewed by 492
Abstract
The circadian clock, an intrinsic 24 h cellular timekeeping system, regulates fundamental biological processes, including tumor physiology and metabolism. Cancer stem cells (CSCs), a subpopulation of cancer cells with self-renewal and tumorigenic capacities, are implicated in tumor initiation, recurrence, and metastasis. Despite growing [...] Read more.
The circadian clock, an intrinsic 24 h cellular timekeeping system, regulates fundamental biological processes, including tumor physiology and metabolism. Cancer stem cells (CSCs), a subpopulation of cancer cells with self-renewal and tumorigenic capacities, are implicated in tumor initiation, recurrence, and metastasis. Despite growing evidence for the circadian clock’s involvement in regulating CSC functions, its precise regulatory mechanisms remain largely unknown. Here, using a human osteosarcoma (OS) model (143B), we have shown that core molecular clock factors are critical for OS stem cell survival and behavior via direct modulation of CSC and lipid metabolic pathways. In single-cell-derived spheroid formation assays, 143B OS cells exhibited robust spheroid-forming capacity under 3D culture conditions. Furthermore, siRNA-mediated depletion of core clock components (i.e., BMAL1, CLOCK, CRY1/2, PER1/2)—essential positive and negative elements of the circadian clock feedback loop—significantly reduced spheroid formation in 143B CSCs isolated from in vivo OS xenografts. In contrast, knockdown of the secondary clock-stabilizing factor genes NR1D1 and NR1D2 had little effect. We also found that knockdown of BMAL1, CLOCK, or CRY1/2 markedly impaired the migration and invasion capacities of 143B CSCs. At the molecular level, silencing of BMAL1, CLOCK, or CRY1/2 distinctly altered the expression of genes associated with stem cell properties and the epithelial–mesenchymal transition (EMT) in 143B CSCs. In addition, disruption of BMAL1, CLOCK, or CRY1/2 expression significantly reduced lipid droplet formation by downregulating the expression of genes involved in lipogenesis (e.g., DGAT1, FASN, ACSL4, PKM2, CHKA, SREBP1), which are closely linked to CSC/EMT processes. Furthermore, transcriptomic analysis of human OS patient samples revealed that compared with other core clock genes, CRY1 was highly expressed in OS tumors relative to controls, and its expression exhibited strong positive correlations with patient prognosis, survival, and LD biogenesis gene expression. These findings highlight the critical role of the molecular circadian clock in regulating CSC properties and metabolism, underscoring the therapeutic potential of targeting the core clock machinery to enhance OS treatment outcomes. Full article
(This article belongs to the Special Issue The Role of Stem Cells and Circadian Clock in Cancer Immunotherapy)
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