Selective depletion of metastatic stem cells as therapy for human colorectal cancer

• Published in: EMBO molecular medicine Vol. 10; no. 10; pp. 1 - n/a
• Main Authors: Céspedes, María Virtudes, Unzueta, Ugutz, Aviñó, Anna, Gallardo, Alberto, Álamo, Patricia, Sala, Rita, Sánchez‐Chardi, Alejandro, Casanova, Isolda, Mangues, María Antònia, Lopez‐Pousa, Antonio, Eritja, Ramón, Villaverde, Antonio, Vázquez, Esther, Mangues, Ramón
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2018; John Wiley & Sons, Inc; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Adjuvant treatment; Animal models; Apoptosis; Cancer; Colorectal cancer; Colorectal carcinoma; CXCR4 protein; CXCR4 receptor; DNA damage; Drug delivery; EMBO03; EMBO12; EMBO39; Genotoxicity; Health aspects; Internalization; Intravenous administration; Liver; Metastases; Metastasis; metastatic stem cells; Patients; Peritoneum; protein nanoconjugate; Research Article; Stem cell transplantation; Stem cells; targeted drug delivery; Transplantation; Tumor cells; CXCR4 receptor; targeted drug delivery; colorectal cancer; protein nanoconjugate; metastatic stem cells
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201708772

Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis‐initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22‐GFP‐H6‐FdU) that selectively delivers Floxuridine to CXCR4 + cells. In contrast to free oligo‐FdU, intravenous T22‐GFP‐H6‐FdU selectively accumulates and internalizes in CXCR4 + cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor re‐initiation capacity. Repeated T22‐GFP‐H6‐FdU administration in cell line and patient‐derived CRC models blocks intravasation and completely prevents metastases development in 38–83% of mice, while showing CXCR4 expression‐dependent and site‐dependent reduction in foci number and size in liver, peritoneal, or lung metastases in the rest of mice, compared to free oligo‐FdU. T22‐GFP‐H6‐FdU induces also higher regression of established metastases than free oligo‐FdU, with negligible distribution or toxicity in normal tissues. This targeted drug delivery approach yields potent antimetastatic effect, through selective depletion of metastatic CXCR4 + cancer cells, and validates metastatic stem cells (MetSCs) as targets for clinical therapy. Synopsis Control of metastatic spread is an unmet need. This study reports on the therapeutic effect of a nanoconjugate (NC) that selectively delivers a drug to metastatic stem cells overexpressing surface CXCR4 receptor (CXCR4 + MetSCs) (Targeted drug delivery) after its intravenous injection in colorectal cancer (CRC) mouse models. Selective NC internalization, leading to a high genotoxic damage and elimination of CXCR4 + CRC cells, in a CXCR4‐dependent way, both in vitro and in vivo . Reduction of tumor re‐initiation capacity and CXCR4 + tumor emboli intravasation in colonic peri‐tumoral vessels after NC treatment. Potent prevention of metastases, in cell line and patient‐derived orthotopic CRC mouse models, yielding a high percent of metastasis‐free mice after repeated‐dose therapy, as compared to the free drug. Metastatic sites with high CXCR4 expression show higher response to the NC and higher reduction in CXCR4 + cancer cell fraction at the end of treatment. Absence of accumulation or toxicity in normal tissues and high therapeutic index achieved by the NC, which exploits the high CXCR4 overexpression in target MetSCs in comparison to non‐tumor cells. Graphical Abstract Control of metastatic spread is an unmet need. This study reports on the therapeutic effect of a nanoconjugate (NC) that selectively delivers a drug to metastatic stem cells overexpressing surface CXCR4 receptor (CXCR4 + MetSCs) (Targeted drug delivery) after its intravenous injection in colorectal cancer (CRC) mouse models.