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Butterfly glioblastoma (bGBM) is a grade 4 glioma with a poor prognosis. Surgical treatment of these cancers has been reviewed in the literature with some recent studies supporting resection as a safe and effective treatment instead of biopsy and adjuvant therapy. This meta-analysis was designed to determine whether there are significant differences in overall survival (OS) and postoperative neurologic deficits (motor, speech, and cranial nerve) following intervention in patients who underwent tumor resection as part of their treatment, compared to patients who underwent biopsy without surgical resection. A literature search was conducted using PubMed (National Library of Medicine) and Embase (Elsevier) to identify articles from each database's earliest records to May 25, 2021, that directly compared the outcomes of biopsy and resection in bGBM patients and met predetermined inclusion criteria. A meta-analysis was conducted to compare the effects of the two management strategies on OS and postoperative neurologic deficits. Six articles met our study inclusion criteria. OS was found to be significantly longer for the resection group at 6 months (odds ratio [OR] 2.94, 95% confidence interval [CI] 1.23-7.05) and 12 months (OR 3.75, 95% CI 1.10-12.76) than for the biopsy group. No statistically significant differences were found in OS at 18 and 24 months. Resection was associated with an increased rate of postoperative neurologic deficit (OR 2.05, 95% CI 1.02-4.09). Resection offers greater OS up to 1 year postintervention than biopsy alone; however, this comes at the cost of higher rates of postoperative neurologic deficits.

Tuberin is a member of a large protein complex, Tuberous Sclerosis Complex (TSC), and acts as a sensor for nutrient status regulating protein synthesis and cell cycle progression. Mutations in the Tuberin gene, TSC2, permits the formation of tumors that can lead to developmental defects in many organ systems, including the central nervous system. Tuberin is expressed in the brain throughout development and levels of Tuberin have been found to decrease during neuronal differentiation in cell lines in vitro. Our current work investigates the levels of Tuberin at two stages of embryonic development in vivo, and we study the mRNA and protein levels during a time course using immortalized cell lines in vitro. Our results show that total Tuberin levels are tightly regulated through developmental stages in the embryonic brain. At a cell biology level, we show that Tuberin levels are higher when cells are cultured as neurospheres, and knockdown of Tuberin results in a reduction in the number of neurospheres. This functional data supports the hypothesis that Tuberin is an important regulator of stemness and the reduction of Tuberin levels might support functional differentiation in the central nervous system. Understanding how Tuberin expression is regulated throughout neural development is essential to fully comprehend the role of this protein in several developmental and neural pathologies.

Glioblastoma is one of the most aggressive types of cancer with median survival of only 15 months. Successful therapy is hampered by the existence of treatment resistant populations of stem-like tumour initiating cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole (DPP)-based conjugated polymer nanoparticles (CPNs) with an average diameter of 109 nm. The CPN were designed to include fluorescein-conjugated hyaluronic acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone decreases stemness, invasive properties and proliferation of the CD44-TIC population in zebrafish PDX models in vivo. This study is the first to show surface moiety-driven selectivity of conjugated polymer nanoparticles in targeting TIC populations in brain cancer.

Glioblastoma is one of the most aggressive types of cancer with median survival of only 15 months. Successful therapy is hampered by the existence of treatment resistant populations of stem-like tumour initiating cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole (DPP)-based conjugated polymer nanoparticles (CPNs) with an average diameter of 109 nm. The CPN were designed to include fluorescein-conjugated hyaluronic acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone decreases stemness, invasive properties and proliferation of the CD44-TIC population in zebrafish PDX models in vivo. This study is the first to show surface moiety-driven selectivity of conjugated polymer nanoparticles in targeting TIC populations in brain cancer.

Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by 18F-FDG than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and 18F-FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported 18F-FDG avidity of PSMA-suppressed tumors. Methods: Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes HK1-HK3 and GCK), and PSMA (FOLH1 gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of GCK and low expression of SLC2A12 correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine-induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of 18F-FDG uptake-associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake.

Fully differentiated cells can be reprogrammed through ectopic expression of key transcription factors to create induced pluripotent stem cells. These cells share many characteristics of normal embryonic stem cells and have great promise in disease modelling and regenerative medicine. The process of remodelling has its limitations, including a very low efficiency due to the upregulation of many anti-proliferative genes, including cyclin dependent kinase inhibitors CDKN1A and CDKN2A, which serve to protect the cell by inducing apoptotic and senescent programs. Our data reveals a unique cell cycle mechanism enabling mouse fibroblasts to repress cyclin dependent kinase inhibitors through the activation of the epigenetic regulator EZH2 by a cyclin-like protein SPY1. This data reveals that the SPY1 protein is required for reprogramming to a pluripotent state and is capable of increasing reprogramming efficiency. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: This work reveals a mechanism used by normal fibroblasts to override reprogramming-induced senescence, thereby increasing the number of cells amenable to becoming induced pluripotent stem cells. Improving efficiencies for deriving pluripotent cells has tremendous potential for economic benefit in regenerative medicine and may reveal mechanisms important in normal development and in various disease states, such as cancer.

Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by (18)F-FDG than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and (18)F-FDG uptake–associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported (18)F-FDG avidity of PSMA-suppressed tumors. Methods: Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes HK1–HK3 and GCK), and PSMA (FOLH1 gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of GCK and low expression of SLC2A12 correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine-induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of (18)F-FDG uptake–associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake.

Neuroblastoma is an aggressive pediatric cancer originating embryonically from the neural crest. The heterogeneity of the disease, as most solid tumors, complicates diagnosis and treatment. In neuroblastoma this heterogeneity is well represented in both primary tumours and derived cell lines and has been shown to be driven by a population of stem-like tumour initiating cells. Resolving the molecular mediators driving the division of this population of cells may indicate effective therapeutic options for neuroblastoma patients. This study has determined that the atypical cyclin-like protein Spy1, recently indicated in driving symmetric division of glioma stem cells, is a critical factor in the stem-like properties of neuroblastoma tumor initiating cell populations. Spy1 activates Cyclin Dependent Kinases (CDK) in a manner that is unique from classical cyclins. Hence this discovery may represent an important opportunity to design CDK inhibitor drugs to uniquely target subpopulations of cells within these aggressive neural tumours.

Summary The heterogeneity of brain cancers, as most solid tumors, complicates diagnosis and treatment. Identifying and targeting populations of cells driving tumorigenesis is a top priority for the cancer biology field. This is not a trivial task; considerable variance exists in the driving mutations, identifying markers, and evolutionary pressures influencing initiating cells in different individual tumors. Despite this, the ability to self-renew and differentiate must be conserved to reseed a heterogeneous tumor mass. Focusing on one example of a tumor-initiating cell population, we demonstrate that the atypical cyclin-like protein Spy1 plays a role in balancing the division properties of glioma cells with stemness properties. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer.

Neuroblastoma is an aggressive pediatric cancer fuelled by inappropriate differentiation of immature cells within the ganglionic lineage. The heterogeneity of the disease, as most cancers, complicates diagnosis and treatment. In neuroblastoma this heterogeneity is well represented in both primary tumors and derived cell lines, and mirrors neural crest plasticity. Multiple studies over the years have attempted to elucidate the molecular basis driving the expansion of the stem-like population within aggressive neuroblastoma; however no study has adequately addressed the role of the core cell cycle machinery. This was the focus of our recent publication in Oncoscience.1 Decreases in activity of the G1/S cyclin dependent kinase (Cdk) Cdk2 and accumulation of the Cdk inhibitor p27Kip,1 supports functional differentiation. Indeed, Cdk2 inhibition is synthetic lethal in MYCN overexpressing neuroblastoma.2 Adult stem cells carefully balance inhibition of the cell cycle with limited expansion in vivo to enable development and regeneration while preventing pathogenesis. The Speedy/RINGO family of ‘cyclin-like’ proteins are capable of binding to and activating the Cdks via a unique mechanism to drive cell growth. Spy1-bound Cdks are not dependent on the classically defined post-translational modifications for activation, nor are they sensitive to suppression by the Cdk inhibitors, quite contrary they can actually promote the degradation of the Cdk inhibitor p27Kip,1 3. Consistent with this guise our group and others have shown that elevated Spy1 levels are capable of overriding numerous forms of senescence.4-6 Why would a cell evolve such a mechanism? We hypothesize that endogenously this may enable expansion of select stem cell populations during development and regeneration, as well as allowing for recovery of a variety of cell types from checkpoint responses. In support of this model, Spy1 has demonstrated roles in spinal cord regeneration and was found to possess stem-like qualities in the developing mammary gland, supporting a general role for Spy1 in select populations of adult stem or progenitor cells.4,7 More recently pathological levels of Spy1 have been implicated in supporting the symmetric expansion of the CD133+ population in human glioma.6 In one of the inaugural issues of Oncoscience we show that Spy1 supports prolonged clonal tumorsphere formation in neuroblastoma cell lines and expands cell populations enriched for markers of multipotency. We find that endogenous Spy1 levels are reduced during guided differentiation of the stem-like population in neuroblastoma and that preventing this downregulation leads to resistance to 13-cis-Retinoic Acid (RA)- induced differentiation. In the mammary gland we have previously reported that Spy1 expression is regulated downstream of c-Myc during normal development. In neuroblastoma we find that c-Myc protein levels correlate with that of Spy1 in all cell lines tested, the relevance for these observations in neuroblastoma pathogenesis remain to be tested. Forced silencing of Spy1 levels in neuroblastoma resulted in a decrease in tumorsphere number, and a reduction in the CD133+ population. Hence, our data supports a novel fundamental role for an atypical cell cycle mechanism in driving expansion of the neural crest stem cells that define the aggressive, drug resistant population in subsets of neuroblastoma. This discovery may represent an important opportunity to design Cdk inhibitor drugs to uniquely target subpopulations of cells within these aggressive neural tumors.

Despite extensive efforts and continual progress in research and medicine, outcomes for patients with high-grade glioma remain exceptionally poor. Over the past decade, research has revealed a great deal about the complex biology behind glioma development, and has brought to light some of the major barriers preventing successful treatment. Glioblastoma multiforme (GBM) (stage 4 astrocytoma) is a highly dynamic tumour and one of the most extreme examples of intratumoural heterogeneity, making targeting with specific therapeutics an inefficient and highly unpredictable goal. The cancer stem cell hypothesis offers a new view on the possible mechanisms dictating the heterogeneous nature of this disease and contributes to our understanding of glioma resistance and recurrence. Revealing cell division characteristics of initiating cell populations within GBM may represent novel treatment targets and/or the effective repurposing of existing therapies. In this review, we discuss the potential role of targeting the cyclin-dependent kinases (CDKs) driving this specific population. We also describe developments using multi-omic approaches that may aid in stratifying patient populations for CDK inhibitor therapy.