Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction
Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular s...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1529847/full |
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| author | Francesco Verona Sebastiano Di Bella Roberto Schirano Camilla Manfredi Francesca Angeloro Giulia Bozzari Matilde Todaro Matilde Todaro Giuseppe Giannini Giuseppe Giannini Giorgio Stassi Veronica Veschi |
| author_facet | Francesco Verona Sebastiano Di Bella Roberto Schirano Camilla Manfredi Francesca Angeloro Giulia Bozzari Matilde Todaro Matilde Todaro Giuseppe Giannini Giuseppe Giannini Giorgio Stassi Veronica Veschi |
| author_sort | Francesco Verona |
| collection | DOAJ |
| description | Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The “oncogenic” immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation. |
| format | Article |
| id | doaj-art-ca3576d034f14253ab10e6b1a69b3cef |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-ca3576d034f14253ab10e6b1a69b3cef2025-02-06T07:10:26ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15298471529847Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interactionFrancesco Verona0Sebastiano Di Bella1Roberto Schirano2Camilla Manfredi3Francesca Angeloro4Giulia Bozzari5Matilde Todaro6Matilde Todaro7Giuseppe Giannini8Giuseppe Giannini9Giorgio Stassi10Veronica Veschi11Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, ItalyDepartment of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, ItalyDepartment of Molecular Medicine, University La Sapienza, Rome, ItalyDepartment of Molecular Medicine, University La Sapienza, Rome, ItalyDepartment of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, ItalyDepartment of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, ItalyDepartment of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, ItalyAzienda Ospedaliera Universitaria Policlinico “Paolo Giaccone” (AOUP), Palermo, ItalyDepartment of Molecular Medicine, University La Sapienza, Rome, ItalyIstituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, ItalyDepartment of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, ItalyDepartment of Molecular Medicine, University La Sapienza, Rome, ItalyCancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The “oncogenic” immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1529847/fullcancer stem cellsTAMssingle-cell RNA sequencing (scRNA-seq)spatial transcriptomicssignaling pathway analysistrajectory analysis |
| spellingShingle | Francesco Verona Sebastiano Di Bella Roberto Schirano Camilla Manfredi Francesca Angeloro Giulia Bozzari Matilde Todaro Matilde Todaro Giuseppe Giannini Giuseppe Giannini Giorgio Stassi Veronica Veschi Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction Frontiers in Immunology cancer stem cells TAMs single-cell RNA sequencing (scRNA-seq) spatial transcriptomics signaling pathway analysis trajectory analysis |
| title | Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction |
| title_full | Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction |
| title_fullStr | Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction |
| title_full_unstemmed | Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction |
| title_short | Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction |
| title_sort | cancer stem cells and tumor associated macrophages as mates in tumor progression mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction |
| topic | cancer stem cells TAMs single-cell RNA sequencing (scRNA-seq) spatial transcriptomics signaling pathway analysis trajectory analysis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1529847/full |
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