Spatial resolution of cellular senescence dynamics in human colorectal liver metastasis

• Published in: Aging cell Vol. 22; no. 7; pp. e13853 - n/a
• Main Authors: Garbarino, Ombretta, Lambroia, Luca, Basso, Gianluca, Marrella, Veronica, Franceschini, Barbara, Soldani, Cristiana, Pasqualini, Fabio, Giuliano, Desiree, Costa, Guido, Peano, Clelia, Barbarossa, Davide, Annarita, Destro, Salvati, Andreina, Terracciano, Luigi, Torzilli, Guido, Donadon, Matteo, Faggioli, Francesca
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2023; John Wiley and Sons Inc
• Subjects: Biopsy; c-Myc protein; Cancer; Cell Line, Tumor; Cellular Senescence; Chemotherapy; Colorectal cancer; colorectal cancer liver metastasis; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA damage; EMT; Epithelial-Mesenchymal Transition; Extracellular matrix; Genes; Histology; Humans; Immunoregulation; Kinases; Liver; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Metastases; Metastasis; Myc protein; NOX4 protein; Nucleoli; Paracrine signalling; prognostic role; Senescence; senescence‐associated secretory phenotype; Spatial data; Spatial discrimination; spatial transcriptomics; Therapeutic targets; Transcriptomics; Ubiquitin; Ubiquitin-protein ligase; cellular senescence; senescence-associated secretory phenotype; prognostic role; EMT; spatial transcriptomics; colorectal cancer liver metastasis
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13853

Hepatic metastasis is a clinical challenge for colorectal cancer (CRC). Senescent cancer cells accumulate in CRC favoring tumor dissemination. Whether this mechanism progresses also in metastasis is unexplored. Here, we integrated spatial transcriptomics, 3D‐microscopy, and multicellular transcriptomics to study the role of cellular senescence in human colorectal liver metastasis (CRLM). We discovered two distinct senescent metastatic cancer cell (SMCC) subtypes, transcriptionally located at the opposite pole of epithelial (e) to mesenchymal (m) transition. SMCCs differ in chemotherapy susceptibility, biological program, and prognostic roles. Mechanistically, epithelial (e)SMCC initiation relies on nucleolar stress, whereby c‐myc dependent oncogene hyperactivation induces ribosomal RPL11 accumulation and DNA damage response. In a 2D pre‐clinical model, we demonstrated that RPL11 co‐localized with HDM2, a p53‐specific ubiquitin ligase, leading to senescence activation in (e)SMCCs. On the contrary, mesenchymal (m)SMCCs undergo TGFβ paracrine activation of NOX4‐p15 effectors. SMCCs display opposing effects also in the immune regulation of neighboring cells, establishing an immunosuppressive environment or leading to an active immune workflow. Both SMCC signatures are predictive biomarkers whose unbalanced ratio determined the clinical outcome in CRLM and CRC patients. Altogether, we provide a comprehensive new understanding of the role of SMCCs in CRLM and highlight their potential as new therapeutic targets to limit CRLM progression. Two distinct senescent cancer ecosystems located at the opposite pole of epithelial (e) to mesenchymal (m) transition duel in metastasis onset of colorectal cancer, defining the immune landscape and the clinical fate of patients.