RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations

Abstract Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway block...

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Autores principales:	Marcus M. Fischer, V. Pete Yeung, Fiore Cattaruzza, Rajaa Hussein, Wan-Ching Yen, Christopher Murriel, James W. Evans, Gilbert O’Young, Alayne L. Brunner, Min Wang, Jennifer Cain, Belinda Cancilla, Ann Kapoun, Timothy Hoey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/97a62eb300e14b3a9c293d6e18060cfa
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spelling	oai:doaj.org-article:97a62eb300e14b3a9c293d6e18060cfa2021-12-02T11:52:32ZRSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations10.1038/s41598-017-15704-y2045-2322https://doaj.org/article/97a62eb300e14b3a9c293d6e18060cfa2017-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-15704-yhttps://doaj.org/toc/2045-2322Abstract Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.Marcus M. FischerV. Pete YeungFiore CattaruzzaRajaa HusseinWan-Ching YenChristopher MurrielJames W. EvansGilbert O’YoungAlayne L. BrunnerMin WangJennifer CainBelinda CancillaAnn KapounTimothy HoeyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marcus M. Fischer V. Pete Yeung Fiore Cattaruzza Rajaa Hussein Wan-Ching Yen Christopher Murriel James W. Evans Gilbert O’Young Alayne L. Brunner Min Wang Jennifer Cain Belinda Cancilla Ann Kapoun Timothy Hoey RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
description	Abstract Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.
format	article
author	Marcus M. Fischer V. Pete Yeung Fiore Cattaruzza Rajaa Hussein Wan-Ching Yen Christopher Murriel James W. Evans Gilbert O’Young Alayne L. Brunner Min Wang Jennifer Cain Belinda Cancilla Ann Kapoun Timothy Hoey
author_facet	Marcus M. Fischer V. Pete Yeung Fiore Cattaruzza Rajaa Hussein Wan-Ching Yen Christopher Murriel James W. Evans Gilbert O’Young Alayne L. Brunner Min Wang Jennifer Cain Belinda Cancilla Ann Kapoun Timothy Hoey
author_sort	Marcus M. Fischer
title	RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
title_short	RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
title_full	RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
title_fullStr	RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
title_full_unstemmed	RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations
title_sort	rspo3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common wnt pathway mutations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/97a62eb300e14b3a9c293d6e18060cfa
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RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations

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