title: Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function.
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.
authors.affiliation: Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Storm
authors.affiliation: Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Durinck
authors.affiliation: Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: de Sousa e Melo
authors.affiliation: Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jarrod
authors.initials: J
authors.lastname: Tremayne
authors.affiliation: Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Noelyn
authors.initials: N
authors.lastname: Kljavin
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tan
authors.affiliation: Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Ye
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Research Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Thinh
authors.initials: T
authors.lastname: Pham
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Hongo
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Bainbridge
authors.affiliation: Research Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.affiliation: Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ciara
authors.initials: C
authors.lastname: Metcalfe
authors.affiliation: Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Stawiski
authors.affiliation: Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.affiliation: Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D019699:Thrombospondins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000098907:R-Spondins
chemical_list: D000906:Antibodies; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D019699:Thrombospondins; C475438:RSPO3 protein, human; D000098907:R-Spondins; C489852:PTPRK protein, human