Niche-derived Soluble DLK1 Promotes Glioma Growth

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2020 Nov 3

PMID 33142235

Citations 7

Authors

Elisa S Grassi

Pauline Jeannot

Vasiliki Pantazopoulou

Tracy J Berg

Alexander Pietras

Affiliations

Soon will be listed here.

Abstract

Tumor cell behaviors associated with aggressive tumor growth such as proliferation, therapeutic resistance, and stem cell characteristics are regulated in part by soluble factors derived from the tumor microenvironment. Tumor-associated astrocytes represent a major component of the glioma tumor microenvironment, and astrocytes have an active role in maintenance of normal neural stem cells in the stem cell niche, in part via secretion of soluble delta-like noncanonical Notch ligand 1 (DLK1). We found that astrocytes, when exposed to stresses of the tumor microenvironment such as hypoxia or ionizing radiation, increased secretion of soluble DLK1. Tumor-associated astrocytes in a glioma mouse model expressed DLK1 in perinecrotic and perivascular tumor areas. Glioma cells exposed to recombinant DLK1 displayed increased proliferation, enhanced self-renewal and colony formation abilities, and increased levels of stem cell marker genes. Mechanistically, DLK1-mediated effects on glioma cells involved increased and prolonged stabilization of hypoxia-inducible factor 2alpha, and inhibition of hypoxia-inducible factor 2alpha activity abolished effects of DLK1 in hypoxia. Forced expression of soluble DLK1 resulted in more aggressive tumor growth and shortened survival in a genetically engineered mouse model of glioma. Together, our data support DLK1 as a soluble mediator of glioma aggressiveness derived from the tumor microenvironment.

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References

Xie Y, Bergstrom T, Jiang Y, Johansson P, Marinescu V, Lindberg N . The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes. EBioMedicine. 2015; 2(10):1351-63. PMC: 4634360. DOI: 10.1016/j.ebiom.2015.08.026. View

Yan Y, Liu F, Han L, Zhao L, Chen J, Olopade O . HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways. J Exp Clin Cancer Res. 2018; 37(1):256. PMC: 6194720. DOI: 10.1186/s13046-018-0925-x. View

Baladron V, Ruiz-Hidalgo M, Nueda M, Diaz-Guerra M, Garcia-Ramirez J, Bonvini E . dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Exp Cell Res. 2005; 303(2):343-59. DOI: 10.1016/j.yexcr.2004.10.001. View

Johansson E, Grassi E, Pantazopoulou V, Tong B, Lindgren D, Berg T . CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells. Cell Rep. 2017; 20(7):1641-1653. DOI: 10.1016/j.celrep.2017.07.049. View

Huse J, Holland E . Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010; 10(5):319-31. DOI: 10.1038/nrc2818. View

Grassi E, Pantazopoulou V, Pietras A . Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma. Oncogene. 2020; 39(20):4028-4044. PMC: 7220882. DOI: 10.1038/s41388-020-1273-9. View

Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S . High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol. 2008; 214(4):482-8. DOI: 10.1002/path.2304. View

Huang C, Cheng S, Wu C, Li W, Wang J, Kung M . Delta-like 1 homologue promotes tumorigenesis and epithelial-mesenchymal transition of ovarian high-grade serous carcinoma through activation of Notch signaling. Oncogene. 2019; 38(17):3201-3215. DOI: 10.1038/s41388-018-0658-5. View

Wang Y, Sul H . Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation. Mol Cell Biol. 2006; 26(14):5421-35. PMC: 1592724. DOI: 10.1128/MCB.02437-05. View

10.

Wallace E, Rizzi J, Han G, Wehn P, Cao Z, Du X . A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma. Cancer Res. 2016; 76(18):5491-500. DOI: 10.1158/0008-5472.CAN-16-0473. View

11.

Jensen R . Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol. 2009; 92(3):317-35. DOI: 10.1007/s11060-009-9827-2. View

12.

Dirkse A, Golebiewska A, Buder T, Nazarov P, Muller A, Poovathingal S . Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nat Commun. 2019; 10(1):1787. PMC: 6467886. DOI: 10.1038/s41467-019-09853-z. View

13.

Yin D, Xie D, Sakajiri S, Miller C, Zhu H, Popoviciu M . DLK1: increased expression in gliomas and associated with oncogenic activities. Oncogene. 2005; 25(13):1852-61. DOI: 10.1038/sj.onc.1209219. View

14.

Das B, Pal B, Bhuyan R, Li H, Sarma A, Gayan S . Regulates the Stemness Pathway via and to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells. Cancer Res. 2019; 79(16):4015-4025. PMC: 6701948. DOI: 10.1158/0008-5472.CAN-18-2847. View

15.

Ozawa T, Riester M, Cheng Y, Huse J, Squatrito M, Helmy K . Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell. 2014; 26(2):288-300. PMC: 4143139. DOI: 10.1016/j.ccr.2014.06.005. View

16.

Katz A, Amankulor N, Pitter K, Helmy K, Squatrito M, Holland E . Astrocyte-specific expression patterns associated with the PDGF-induced glioma microenvironment. PLoS One. 2012; 7(2):e32453. PMC: 3290579. DOI: 10.1371/journal.pone.0032453. View

17.

Kim Y, Lin Q, Zelterman D, Yun Z . Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity. Cancer Res. 2009; 69(24):9271-80. PMC: 2828615. DOI: 10.1158/0008-5472.CAN-09-1605. View

18.

Bernstock J, Mooney J, Ilyas A, Chagoya G, Estevez-Ordonez D, Ibrahim A . Molecular and cellular intratumoral heterogeneity in primary glioblastoma: clinical and translational implications. J Neurosurg. 2019; 133(3):655-663. DOI: 10.3171/2019.5.JNS19364. View

19.

Hira V, Breznik B, Vittori M, Loncq de Jong A, Mlakar J, Oostra R . Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies. J Histochem Cytochem. 2019; 68(1):33-57. PMC: 6931169. DOI: 10.1369/0022155419878416. View

20.

Hambardzumyan D, Bergers G . Glioblastoma: Defining Tumor Niches. Trends Cancer. 2016; 1(4):252-265. PMC: 4831073. DOI: 10.1016/j.trecan.2015.10.009. View