Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells

Nicholas Borcherding; David Kusner; Ryan Kolb; Qing Xie; Wei Li; Fang Yuan; Gabriel Velez; Ryan Askeland; Ronald J Weigel; Weizhou Zhang

doi:10.1158/0008-5472.CAN-14-2761

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Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells

Journal article

Open access

Peer reviewed

Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells

Nicholas Borcherding, David Kusner, Ryan Kolb, Qing Xie, Wei Li, Fang Yuan, Gabriel Velez, Ryan Askeland, Ronald J Weigel and Weizhou Zhang

Cancer research (Chicago, Ill.), Vol.75(10), pp.1972-1982

05/15/2015

DOI: 10.1158/0008-5472.CAN-14-2761

PMCID: PMC4433621

PMID: 25769722

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https://doi.org/10.1158/0008-5472.CAN-14-2761View

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Abstract

It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared with the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of the TGFβ-SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal-luminal cross-talk in normal mammary tissue.

Cell Proliferation

Paracrine Communication

Lung Neoplasms - mortality

Lung Neoplasms - metabolism

Mice, Inbred C57BL

Kaplan-Meier Estimate

Smad2 Protein - metabolism

Transcriptome

Transforming Growth Factor beta - physiology

Wnt-5a Protein

Breast Neoplasms - metabolism

Animals

Lung Neoplasms - secondary

Breast Neoplasms - pathology

Proto-Oncogene Proteins - physiology

Breast Neoplasms - mortality

Female

Wnt Proteins - physiology

Neoplastic Stem Cells - physiology

Details

Title: Subtitle: Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells
Creators: Nicholas Borcherding - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa
David Kusner - University of Iowa, Internal Medicine
Ryan Kolb - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Immunology Program, University of Iowa, College of Medicine, Iowa City, Iowa
Qing Xie - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, P.R. China
Wei Li - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa
Fang Yuan - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
Gabriel Velez - Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa
Ryan Askeland - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa
Ronald J Weigel - Department of Surgery, University of Iowa, College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, Iowa
Weizhou Zhang - Department of Pathology, University of Iowa, College of Medicine, Iowa City, Iowa. Medical Science Training Program, University of Iowa, College of Medicine, Iowa City, Iowa. Molecular and Cellular Biology Program, University of Iowa, College of Medicine, Iowa City, Iowa. Immunology Program, University of Iowa, College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, Iowa. weizhou-zhang@uiowa.edu
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.75(10), pp.1972-1982
DOI: 10.1158/0008-5472.CAN-14-2761
PMID: 25769722
PMCID: PMC4433621
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: R00 CA158055 / NCI NIH HHS S10 RR027219 / NCRR NIH HHS 1S10 RR027219 / NCRR NIH HHS T32 CA148062 / NCI NIH HHS T32 AI007260 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS K99 CA158055 / NCI NIH HHS K99/R00 CA158055 / NCI NIH HHS P30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 05/15/2015
Academic Unit: Dermatology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Surgery; Radiation Oncology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984024552302771

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