Publication Date:
2015-12-25
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Storm, Elaine E -- Durinck, Steffen -- de Sousa e Melo, Felipe -- Tremayne, Jarrod -- Kljavin, Noelyn -- Tan, Christine -- Ye, Xiaofen -- Chiu, Cecilia -- Pham, Thinh -- Hongo, Jo-Anne -- Bainbridge, Travis -- Firestein, Ron -- Blackwood, Elizabeth -- Metcalfe, Ciara -- Stawiski, Eric W -- Yauch, Robert L -- Wu, Yan -- de Sauvage, Frederic J -- England -- Nature. 2016 Jan 7;529(7584):97-100. doi: 10.1038/nature16466. Epub 2015 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Research Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26700806" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibodies/immunology/pharmacology/therapeutic use
;
Cell Differentiation/*drug effects
;
Cell Division/drug effects
;
Colorectal Neoplasms/*drug therapy/metabolism/*pathology
;
Disease Progression
;
Female
;
Gene Expression Regulation/drug effects
;
Humans
;
Intestines/cytology/drug effects/metabolism/pathology
;
Male
;
Mice
;
*Molecular Targeted Therapy
;
Neoplastic Stem Cells/*drug effects/metabolism/*pathology
;
Receptor-Like Protein Tyrosine Phosphatases, Class 2/*metabolism
;
Stem Cells/cytology/metabolism
;
Thrombospondins/antagonists & inhibitors/immunology/*metabolism
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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