HMMR Maintains the Stemness and Tumorigenicity of Glioblastoma Stem-like Cells

Tilghman, Jessica; Wu, Hao; Sang, Yingying; Shi, Xiaohai; Guerrero-Cázares, Hugo; Quiñones‐Hinojosa, Alfredo; Eberhart, Charles G.; Laterra, John; Ying, Mingyao

doi:10.1158/0008-5472.can-13-2103

Cited by 115 publications

(110 citation statements)

References 66 publications

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“…reinforces the need to create defined extracellular matrix environments to study the dynamic response of GBM cells to EGFR inhibitors. [45,46] Together, these findings suggest inhibition of proliferation and migration by erlotinib is influenced by matrix composition, subject to the presence of vIII mutation, with proliferation findings consistent with previously reported mouse model results. [40] Alternatively, cells were exposed to erlotinib continuously for the 10 day period (media was changed at days 3 and 7, comparable to cyclic experiments) to assess potential differences between dosing schedule (cyclic vs. continuous).…”

Section: Erlotinib Inhibits Proliferation and Migration Of Egfr+ Gbmsupporting

confidence: 90%

Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens

Pedrón

Wolter

Chen

et al. 2019

Preprint

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Therapeutic options to treat primary glioblastoma (GBM) tumors are scarce. GBM tumors with epidermal growth factor receptor (EGFR) mutations, in particular a constitutively active EGFRvIII mutant, have extremely poor clinical outcomes. GBM tumors with concurrent EGFR amplification and active phosphatase and tensin homolog (PTEN) are sensitive to the tyrosine kinase inhibitor erlotinib, but the effect is not durable. A persistent challenge to improved treatment is the poorly understood role of cellular, metabolic, and biophysical signals from the GBM tumor microenvironment on therapeutic efficacy and acquired resistance. The intractable nature of studying GBM cell in vivo motivates tissue engineering approaches to replicate aspects of the complex GBM tumor microenvironment. Here, we profile the effect of erlotinib on two patient-derived GBM specimens: EGFR+ GBM12 and EGFRvIII GBM6. We use a threedimensional gelatin hydrogel to present brain-mimetic hyaluronic acid (HA) and evaluate the coordinated influence of extracellular matrix signals and EGFR mutation status on GBM cell migration, survival and proliferation, as well as signaling pathway activation in response to cyclic erlotinib exposure. Comparable to results observed in vivo for xenograft tumors, erlotinib exposure is not cytotoxic for GBM6 EGFRvIII specimens. We also identify a role of extracellular HA (via CD44) in altering the effect of erlotinib in GBM EGFR+ cells by modifying STAT3 phosphorylation status. Taken together, we report an in vitro tissue engineered platform to monitor signaling associated with poor response to targeted inhibitors in GBM.

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Section: Erlotinib Inhibits Proliferation and Migration Of Egfr+ Gbmsupporting

confidence: 90%

Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens

Pedrón

Wolter

Chen

et al. 2019

Preprint

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“…RHAMM upregulation is commonly observed in cancers, including mammary (27), prostate (28), colorectal (29), hepatocellular (30) carcinomas, and glioblastomas (31), whereas deletion of the RHAMM locus has been reported in malignant nerve sheath tumors (32). We thus extended the RHAMM expression analysis to 42 human testis biopsy samples (Supplementary Table S1), comprising seminomas ("pure" GC tumors; Fig.…”

Section: Resultsmentioning

confidence: 99%

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Frappart

Moll

et al. 2016

Cancer Research

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Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM-a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting selfrenewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382-95. Ó2016 AACR.

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“…These lncRNAs and their neighboring protein-coding genes form “lncRNA–mRNA gene pairs”, which interplay with each other in the process of tumors 23–25. It was reported that the protein-coding gene HMMR could interplay with the critical cancer driver genes BRCA1/2 in BLBC15 and the function of HMMR is involved in the progression of breast cancer, colorectal cancer, and glioma 26–28. Thus, it is tempting to speculate that lncRNA HMMR-AS1 and HMMR may be correlated with each other to effect the progression of BLBCs.…”

Section: Discussionmentioning

confidence: 99%

HMMR antisense RNA 1, a novel long noncoding RNA, regulates the progression of basal-like breast cancer cells

Liu¹,

Ma²,

Cheng³

et al. 2016

BCTT

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Recently, accumulating evidence has suggested that long noncoding RNAs (lncRNAs) play crucial roles in carcinogenesis and cancer progression. Hyaluronan-mediated motility receptor (HMMR) is an essential cancer-related gene in basal-like breast cancer (BLBC). In our study, HMMR antisense RNA 1 (HMMR-AS1) was analyzed in BLBC patients through polymerase chain reaction analysis. Here, we found that the expression of HMMR was positively correlated with HMMR-AS1 (RP11-80G.1). When HMMR-AS1 (RP11-80G.1) was knocked down, the expression of HMMR markedly reduced. Furthermore, in MDA-MB-231 and MDA-MB-468 breast cancer cells, the proliferation and migration abilities were remarkably suppressed via knocking down HMMR-AS1 (RP11-80G.1) in vitro. The results showed that lncRNA HMMR-AS1 (RP11-80G.1) influenced the progression of BLBCs through regulating HMMR, suggesting that HMMR-AS1 (RP11-80G.1) could be regarded as a novel biomarker and therapeutic target in the treatment of BLBCs in future.

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HMMR Maintains the Stemness and Tumorigenicity of Glioblastoma Stem-like Cells

Cited by 115 publications

References 66 publications

Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens

Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

HMMR antisense RNA 1, a novel long noncoding RNA, regulates the progression of basal-like breast cancer cells

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