2. Academic Validation
  3. C1Q+ TPP1+ macrophages promote colon cancer progression through SETD8-driven p53 methylation

C1Q+ TPP1+ macrophages promote colon cancer progression through SETD8-driven p53 methylation

  • Mol Cancer. 2025 Mar 31;24(1):102. doi: 10.1186/s12943-025-02293-y.
Veronica Veschi # 1 2,  Francesco Verona # 3,  Sebastiano Di Bella 4,  Alice Turdo 3,  Miriam Gaggianesi 4,  Simone Di Franco 4,  Laura Rosa Mangiapane 3,  Chiara Modica 4,  Melania Lo Iacono 3,  Paola Bianca 3,  Ornella Roberta Brancato 4,  Caterina D'Accardo 3,  Gaetana Porcelli 3,  Vincenzo Luca Lentini 5,  Isabella Sperduti 6,  Elisabetta Sciacca 7,  Peter Fitzgerald 8,  David Lopez-Perez 9,  Pierre Martine 9,  Kate Brown 9,  Giuseppe Giannini 10 11,  Ettore Appella 9,  Giorgio Stassi # 12,  Matilde Todaro # 3 13
Affiliations

Affiliations

  • 1 Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, 90127, Italy. [email protected].
  • 2 Department of Molecular Medicine, University of Rome La Sapienza, Rome, 00161, Italy. [email protected].
  • 3 Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, 90127, Italy.
  • 4 Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, 90127, Italy.
  • 5 Villa Sofia-Cervello Hospital, Palermo, 90146, Italy.
  • 6 Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS - Regina Elena National Cancer Institute, Rome, 00144, Italy.
  • 7 Centre for Experimental Medicine and Rheumatology, the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, Bartsand, London, UK.
  • 8 Genome Analysis Unit, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 9 Chemical Immunology Section, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD, USA.
  • 10 Department of Molecular Medicine, University of Rome La Sapienza, Rome, 00161, Italy.
  • 11 Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, Rome, 00161, Italy.
  • 12 Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, 90127, Italy. [email protected].
  • 13 Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone" (AOUP), Palermo, Italy.
  • # Contributed equally.
PMID: 40165182 DOI: 10.1186/s12943-025-02293-y
Abstract

Background: In many tumors, the tumor suppressor TP53 is not mutated, but functionally inactivated. However, mechanisms underlying p53 functional inactivation remain poorly understood. SETD8 is the sole enzyme known to mono-methylate p53 on lysine 382 (p53K382me1), resulting in the inhibition of its pro-apoptotic and growth-arresting functions.

Methods: We analyzed SETD8 and p53K382me1 expression in clinical colorectal Cancer (CRC) and inflammatory bowel disease (IBD) samples. Histopathological examinations, RNA Sequencing, ChIP assay and preclinical in vivo CRC models, were used to assess the functional role of p53 inactivation in tumor cells and immune cell infiltration.

Results: By integrating bulk RNAseq and scRNAseq approaches in CRC patients, SETD8-mediated p53 regulation resulted the most significantly enriched pathway. p53K382me1 expression was confined to colorectal Cancer Stem Cells (CR-CSCs) and C1q+ TPP1+ tumor-associated macrophages (TAMs) in CRC patient tissues, with high levels predicting decreased survival probability. TAMs promote p53 functional inactivation in CR-CSCs through IL-6 and MCP-1 secretion and increased levels of CEBPD, which directly binds SETD8 promoter thus enhancing its transcription. The direct binding of C1q present on macrophages and C1q receptor (C1QR) present on Cancer Stem Cells mediates the cross-talk between the two cell compartments. As monotherapy, SETD8 genetic and pharmacological (UNC0379) inhibition affects the tumor growth and metastasis formation in CRC mouse avatars, with enhanced effects observed when combined with IL-6 receptor targeting.

Conclusions: These findings suggest that p53K382me1 may be an early step in tumor initiation, especially in inflammation-induced CRC, and could serve as a functional biomarker and therapeutic target in Adjuvant setting for advanced CRCs.

Keywords

C1Q+ TPP1+ macrophages; CRC; Cancer stem cells; IBD; P53K382me1; SETD8.

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