Sema3C Signaling is an Alternative Activator of the Canonical WNT Pathway in Glioblastoma

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Apr 20

PMID 37080989

Authors

Jing Hao

Xiangzi Han

Haidong Huang

Xingjiang Yu

Jiankang Fang

Jianjun Zhao

Richard A Prayson

Shideng Bao

Jennifer S Yu

Affiliations

Soon will be listed here.

Abstract

The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Wnt inhibitors have uniformly failed in clinical trials. Here, we report a mechanism of WNT pathway activation through the Semaphorin 3 C neurodevelopmental program in glioma stem-like cells. Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent process, leading to transactivation of Wnt target genes. Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C drives canonical Wnt signaling independent of Wnt ligand binding. In a mouse model of glioblastoma, combined depletion of Sema3C and β-catenin partner TCF1 extended animal survival more than single target inhibition alone. In human glioblastoma, Sema3C expression and Wnt pathway activation were highly concordant. Since Sema3C is frequently overexpressed in glioblastoma, Sema3C signaling may be a significant mechanism of resistance to upstream Wnt pathway inhibitors. Dual targeting of Sema3C and Wnt pathways may achieve clinically significant Wnt pathway inhibition.

Citing Articles

KLF6-mediated recruitment of the p300 complex enhances H3K23su and cooperatively upregulates SEMA3C with FOSL2 to drive 5-FU resistance in colon cancer cells.

Zhang B, Qi T, Lin J, Zhai S, Wang X, Zhou L Exp Mol Med. 2025; .

PMID: 40082673 DOI: 10.1038/s12276-025-01424-1.

Multiple-testing corrections in selection scans using identity-by-descent segments.

Temple S, Browning S bioRxiv. 2025; .

PMID: 39975073 PMC: 11838353. DOI: 10.1101/2025.01.29.635528.

Deciphering the dose-dependent effects of thymoquinone on cellular proliferation and transcriptomic changes in A172 glioblastoma cells.

Pandey R, Natarajan P, Reddy U, Du W, Sirbu C, Sissoko M PLoS One. 2025; 20(1):e0318185.

PMID: 39874307 PMC: 11774404. DOI: 10.1371/journal.pone.0318185.

Spatial transcriptomics reveals unique metabolic profile and key oncogenic regulators of cervical squamous cell carcinoma.

Zhou L, Liu J, Yao P, Liu X, Chen F, Chen Y J Transl Med. 2024; 22(1):1163.

PMID: 39741285 PMC: 11687147. DOI: 10.1186/s12967-024-06011-y.

Emerging roles and biomarker potential of WNT6 in human cancers.

Ferreira J, Goncalves C, Costa B Cell Commun Signal. 2024; 22(1):538.

PMID: 39529066 PMC: 11552340. DOI: 10.1186/s12964-024-01892-4.

References

Chen J, Li Y, Yu T, McKay R, Burns D, Kernie S . A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012; 488(7412):522-6. PMC: 3427400. DOI: 10.1038/nature11287. View

Kaur N, Chettiar S, Rathod S, Rath P, Muzumdar D, Shaikh M . Wnt3a mediated activation of Wnt/β-catenin signaling promotes tumor progression in glioblastoma. Mol Cell Neurosci. 2013; 54:44-57. DOI: 10.1016/j.mcn.2013.01.001. View

Mire E, Hocine M, Bazellieres E, Jungas T, Davy A, Chauvet S . Developmental Upregulation of Ephrin-B1 Silences Sema3C/Neuropilin-1 Signaling during Post-crossing Navigation of Corpus Callosum Axons. Curr Biol. 2018; 28(11):1768-1782.e4. DOI: 10.1016/j.cub.2018.04.026. View

Batlle E, Clevers H . Cancer stem cells revisited. Nat Med. 2017; 23(10):1124-1134. DOI: 10.1038/nm.4409. View

Miyato H, Tsuno N, Kitayama J . Semaphorin 3C is involved in the progression of gastric cancer. Cancer Sci. 2012; 103(11):1961-6. PMC: 7659286. DOI: 10.1111/cas.12003. View

Schwartz M, Meredith J, Kiosses W . An activated Rac mutant functions as a dominant negative for membrane ruffling. Oncogene. 1998; 17(5):625-9. DOI: 10.1038/sj.onc.1201977. View

Gong A, Huang S . FoxM1 and Wnt/β-catenin signaling in glioma stem cells. Cancer Res. 2012; 72(22):5658-62. PMC: 3500394. DOI: 10.1158/0008-5472.CAN-12-0953. View

Kahn M . Can we safely target the WNT pathway?. Nat Rev Drug Discov. 2014; 13(7):513-32. PMC: 4426976. DOI: 10.1038/nrd4233. View

Kim K, Seol H, Kim E, Rheey J, Jin H, Lee Y . Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells. Neuro Oncol. 2012; 15(2):161-71. PMC: 3548587. DOI: 10.1093/neuonc/nos299. View

10.

Clevers H, Nusse R . Wnt/β-catenin signaling and disease. Cell. 2012; 149(6):1192-205. DOI: 10.1016/j.cell.2012.05.012. View

11.

Blanc V, Nariculam J, Munson P, Freeman A, Klocker H, Masters J . A role for class 3 semaphorins in prostate cancer. Prostate. 2010; 71(6):649-58. DOI: 10.1002/pros.21281. View

12.

Zhan T, Rindtorff N, Boutros M . Wnt signaling in cancer. Oncogene. 2016; 36(11):1461-1473. PMC: 5357762. DOI: 10.1038/onc.2016.304. View

13.

Tran T, Rubio M, Clem R, Johnson D, Case L, Tessier-Lavigne M . Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature. 2009; 462(7276):1065-9. PMC: 2842559. DOI: 10.1038/nature08628. View

14.

Cadigan K . TCFs and Wnt/β-catenin signaling: more than one way to throw the switch. Curr Top Dev Biol. 2012; 98:1-34. DOI: 10.1016/B978-0-12-386499-4.00001-X. View

15.

Liu J, Pan S, Hsieh M, Ng N, Sun F, Wang T . Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013; 110(50):20224-9. PMC: 3864356. DOI: 10.1073/pnas.1314239110. View

16.

Wiegreffe C, Simon R, Peschkes K, Kling C, Strehle M, Cheng J . Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c. Neuron. 2015; 87(2):311-25. DOI: 10.1016/j.neuron.2015.06.023. View

17.

Smithers C, Overduin M . Structural Mechanisms and Drug Discovery Prospects of Rho GTPases. Cells. 2016; 5(2). PMC: 4931675. DOI: 10.3390/cells5020026. View

18.

Jung Y, Park J . Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med. 2020; 52(2):183-191. PMC: 7062731. DOI: 10.1038/s12276-020-0380-6. View

19.

Esselens C, Malapeira J, Colome N, Casal C, Rodriguez-Manzaneque J, Canals F . The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem. 2009; 285(4):2463-73. PMC: 2807303. DOI: 10.1074/jbc.M109.055129. View

20.

Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G . Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006; 13(7):1238-41. DOI: 10.1038/sj.cdd.4401872. View