Abstract
Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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Antibodies / therapeutic use
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Cell Differentiation / drug effects*
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Cell Division / drug effects
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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Disease Progression
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Female
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Gene Expression Regulation / drug effects
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Humans
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Intestinal Mucosa / metabolism
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Intestines / cytology
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Intestines / drug effects
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Intestines / pathology
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Male
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Mice
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Molecular Targeted Therapy*
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*
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Stem Cells / cytology
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Stem Cells / metabolism
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Thrombospondins / antagonists & inhibitors
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Thrombospondins / immunology
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Thrombospondins / metabolism*
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Xenograft Model Antitumor Assays
Substances
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Antibodies
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RSPO3 protein, human
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Thrombospondins
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PTPRK protein, human
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Receptor-Like Protein Tyrosine Phosphatases, Class 2