Peter Wend

UCLA Jonsson Comprehensive Cancer Center

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i-10 index

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Susan A. Krum

University of Tennessee Health Science Center

Gustavo A. Miranda‐Carboni

University of Tennessee Health Science Center

Stephan Lehr

Baxter (Austria)

Tiffany N. Seagroves

University of Tennessee Health Science Center

Stephanie Runke

University of Arizona

Iram Fatima

University of Nebraska Medical Center

Raisa I. Krutilina

University of Tennessee Health Science Center

Victoria L. Seewaldt

City of Hope

William L. Kuenzinger

University of Tennessee Health Science Center

Jackelyn A. Alva-Ornelas

City of Hope

Cooperative Institutions

Max Delbrück Center

University of California, Los Angeles

University of Tennessee Health Science Center

Center for Cancer Research

Charité - Universitätsmedizin Berlin

UCLA Jonsson Comprehensive Cancer Center

Heidelberg University

UCLA Health

Freie Universität Berlin

Istituto di Chimica Biomolecolare

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Intracellular glycine receptor function facilitates glioma formation in vivo

Journal of Cell Science (2014)

Benjamín Förstera Omar Dzaye Aline Winkelmann Marcus Semtner Bruno Benedetti

The neuronal function of Cys-loop neurotransmitter receptors is established; however, their role in non-neuronal cells is poorly defined. As brain tumors accumulate the neurotransmitter glycine, we studied expression and function of glycine receptors (GlyR) in glioma cells. Human brain tumor biopsies selectively expressed GlyR subunits with nuclear import signal (NLS, α1 and α3). The mouse glioma cell line GL261 expressed GlyR α1, and knock-down of α1 protein expression impaired self-renewal capacity and tumorigenicity of GL261 glioma cells as evidenced by the neurosphere assay and GL261 cell inoculation in vivo, respectively. We furthermore show that the pronounced tumorigenic effect of GlyR α1 relies on a new intracellular signaling function that depends on the NLS region in the large cytosolic loop and impacts on GL261 glioma cell gene regulation. Stable expression of GlyR α1 and α3 loops rescued self-renewal capacity of GlyR α1 knock-down cells, which demonstrates their functional equivalence. The new intracellular signaling function identified here goes beyond the well-established role of GlyRs as neuronal ligand-gated ion channels and defines NLS-containing GlyRs as novel potential targets for brain tumor therapies.

Neurotransmitter receptor

HEK 293 cells

10.1242/jcs.146662

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Citations (17)

Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours

The EMBO Journal (2013)

Peter Wend Liang Fang Qionghua Zhu Jörg Schipper Christoph Loddenkemper

Beta-catenin

H3K4me3

10.1038/emboj.2013.127

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Citations (90)

Wnt signaling in stem and cancer stem cells

Seminars in Cell and Developmental Biology (2010)

Peter Wend Jane D. Holland Ulrike Ziebold Walter Birchmeier

Induced stem cells

10.1016/j.semcdb.2010.09.004

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Citations (222)

Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of β-catenin in mice

Genes & Development (2008)

Tamara Grigoryan Peter Wend Alexandra Klaus‐Bergmann Walter Birchmeier

Wnt signaling is one of a handful of powerful signaling pathways that play crucial roles in the animal life by controlling the genetic programs of embryonic development and adult homeostasis. When disrupted, these signaling pathways cause developmental defects, or diseases, among them cancer. The gateway of the canonical Wnt pathway, which contains >100 genes, is an essential molecule called β-catenin (Armadillo in Drosophila ). Conditional loss- and gain-of-function mutations of β-catenin in mice provided powerful tools for the functional analysis of canonical Wnt signaling in many tissues and organs. Such studies revealed roles of Wnt signaling that were previously not accessible to genetic analysis due to the early embryonic lethality of conventional β-catenin knockout mice, as well as the redundancy of Wnt ligands, receptors, and transcription factors. Analysis of conditional β-catenin loss- and gain-of-function mutant mice demonstrated that canonical Wnt signals control progenitor cell expansion and lineage decisions both in the early embryo and in many organs. Canonical Wnt signaling also plays important roles in the maintenance of various embryonic or adult stem cells, and as recent findings demonstrated, in cancer stem cell types. This has opened new opportunities to model numerous human diseases, which have been associated with deregulated Wnt signaling. Our review summarizes what has been learned from genetic studies of the Wnt pathway by the analysis of conditional β-catenin loss- and gain-of-function mice.

Beta-catenin

LRP6

Conditional gene knockout

AXIN2

LRP5

10.1101/gad.1686208

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Citations (549)

Supplementary Data from The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Ikbale El Ayachi Iram Fatima Peter Wend Jackelyn A. Alva-Ornelas Stephanie Runke

Supplementary Section: 1) Seven supplementary figures and legends: A. Supplementary figure S1: TCGA analysis of WNT10B network. B. Supplementary figure S2: Human IHC analysis of WNT10B, HMGA2 and EZH2. C. Supplementary figure S3: Mouse IHC analysis of HMGA2 and EZH2. D. Supplementary figure S4: ChIP, qPCR and IB analysis on WNT10B/ï�¢CATENIN direct target genes. E. Supplementary figure S5: Characterization of CRISPR HMGA2KO and EZH2KO cells both in vitro and in vivo. F. Supplementary figure S6: Validation of WNT10B network on TNBC PDX tumors. G. Supplementary figure S7: Isobologram curves of ICG-001 and Doxorubicin activity. 2) Supplementary Material & Methods 3) Supplementary Table 1 (ST1) qPCR primers 4) Supplementary Table 2 (ST2) ChIP primers 5) 6) Supplementary Table 3 (ST3) drug combinatorial index

10.1158/0008-5472.22422239

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The role of WNT10B in physiology and disease

Acta Physiologica (2011)

Peter Wend Korinna Wend Susan A. Krum Gustavo A. Miranda‐Carboni

Wnt10b is a member of the Wnt ligand gene family that encodes for secreted proteins, which activate the ancient and highly conserved Wnt signalling cascade. The Wnt pathway has been shown to be essential for embryonic development, tissue integrity, and stem cell activity, but if deregulated, also causes disease such as cancer. Although the 19 different Wnt ligands found in both human and mouse can activate several branches of the Wnt pathway, WNT10B specifically activates canonical Wnt/β-catenin signalling and thus triggers β-catenin/LEF/TCF-mediated transcriptional programs. In this review, we highlight the unique functions of WNT10B and mechanisms of how WNT10B acts in the immune system, mammary gland, adipose tissue, bone and skin. In these organs, WNT10B has been well established to be involved in signalling networks controlling stemness, pluripotency and cell fate decisions. Deregulation of these processes causes diseases such as breast cancer, obesity and osteoporosis. Compelling evidence suggests that WNT10B is a valuable candidate for the development of therapeutic regimens for human diseases.

10.1111/j.1748-1716.2011.02296.x

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Citations (94)

Data from The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Ikbale El Ayachi Iram Fatima Peter Wend Jackelyn A. Alva-Ornelas Stephanie Runke

<div>AbstractTriple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.Significance:These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.</div>

HMGA2

Triple-negative breast cancer

10.1158/0008-5472.c.6511163.v1

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ERα regulates lipid metabolism in bone through ATGL and perilipin

Journal of Cellular Biochemistry (2013)

Korinna Wend Peter Wend Brian G. Drew Andrea L. Hevener Gustavo A. Miranda‐Carboni

A decrease in bone mineral density during menopause is accompanied by an increase in adipocytes in the bone marrow space. Ovariectomy also leads to accumulation of fat in the bone marrow. Herein we show increased lipid accumulation in bone marrow from estrogen receptor alpha (ERα) knockout (ERαKO) mice compared to wild-type (WT) mice or estrogen receptor beta (ERβ) knockout (ERβKO) mice. Similarly, bone marrow cells from ERαKO mice differentiated to adipocytes in culture also have increased lipid accumulation compared to cells from WT mice or ERβKO mice. Analysis of individual adipocytes shows that WT mice have fewer, but larger, lipid droplets per cell than adipocytes from ERαKO or ERβKO animals. Furthermore, higher levels of adipose triglyceride lipase (ATGL) protein in WT adipocytes correlate with increased lipolysis and fewer lipid droplets per cell and treatment with 17β-estradiol (E2) potentiates this response. In contrast, cells from ERαKO mice display higher perilipin protein levels, promoting lipogenesis. Together these results demonstrate that E2 signals via ERα to regulate lipid droplet size and total lipid accumulation in the bone marrow space in vivo.

Perilipin

Adipose triglyceride lipase

Lipid droplet

Knockout mouse

10.1002/jcb.24470

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Citations (37)

Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells

Brain (2010)

Sridhar Reddy Chirasani Alexander Sternjak Peter Wend Stefan Momma Benito Campos

Glioblastoma cells with stem-like properties control brain tumour growth and recurrence. Here, we show that endogenous neural precursor cells perform an anti-tumour response by specifically targeting stem-like brain tumour cells. In vitro, neural precursor cells predominantly express bone morphogenetic protein-7; bone morphogenetic protein-7 is constitutively released from neurospheres and induces canonical bone morphogenetic protein signalling in stem-like glioblastoma cells. Exposure of human and murine stem-like brain tumour cells to neurosphere-derived bone morphogenetic protein-7 induces tumour stem cell differentiation, attenuates stem-like marker expression and reduces self-renewal and the ability for tumour initiation. Neurosphere-derived or recombinant bone morphogenetic protein-7 reduces glioblastoma expansion from stem-like cells by down-regulating the transcription factor Olig2. In vivo, large numbers of bone morphogenetic protein-7-expressing neural precursors encircle brain tumours in young mice, induce canonical bone morphogenetic protein signalling in stem-like glioblastoma cells and can thereby attenuate tumour formation. This anti-tumour response is strongly reduced in older mice. Our results indicate that endogenous neural precursor cells protect the young brain from glioblastoma by releasing bone morphogenetic protein-7, which acts as a paracrine tumour suppressor that represses proliferation, self-renewal and tumour-initiation of stem-like glioblastoma cells.

Neurosphere

10.1093/brain/awq128

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Citations (96)

Supplementary Data from The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

Ikbale El Ayachi Iram Fatima Peter Wend Jackelyn A. Alva-Ornelas Stephanie Runke

HMGA2

10.1158/0008-5472.22422239.v1

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Citations (0)