Abstract Recent research has shown a role of proteasome ubiquitination in medulloblastoma tumorigenesis and proteasome inhibition as a possible therapeutic target. In medulloblastoma primary cell culture and in a Patched1 haploinsufficiency medulloblastoma mice model, bortezomib, a proteasome inhibitor, has been shown to limit tumor growth via induction of apoptosis and inhibition of cell proliferation. However, its clinical utility is limited by its inability to cross the blood brain barrier and association with peripheral neuropathy. Marizomib, a more lipophilic proteasome inhibitor, has been shown to cross the blood brain barrier in preclinical studies and is being used in Phase III studies for adult glioblastoma in combination with radiation and temozolomide. Here, we evaluated dose dependent cell killing of marizomib in two group 3, myc-amplified medulloblastoma cell cultures. IC50’s were determined and were consistent with and slightly lower than that seen in adult glioblastoma cell cultures. We suggest marizomib warrants further investigation as a potential therapeutic target for recurrent medulloblastoma. Future studies will include determination of IC50’s for marizomib in cell lines for all medulloblastoma molecular subgroups and primary cell cultures as well as in vitro testing with patient-derived xenograft models.

The clinical benefits of the MammaPrint^® signature for breast cancer is well documented; however, how these genes are related to cell cycle perturbation have not been well determined. Our single-cell transcriptome mapping (algorithm) provides details into the fine perturbation of all individual genes during a cell cycle, providing a view of the cell-cycle-phase specific landscape of any given human genes. Specifically, we identified that 38 out of the 70 (54%) MammaPrint^® signature genes are perturbated to a specific phase of the cell cycle. The MammaPrint^® signature panel derived its clinical prognosis power from measuring the cell cycle activity of specific breast cancer samples. Such cell cycle phase index of the MammaPrint^® signature suggested that measurement of the cell cycle index from tumors could be developed into a prognosis tool for various types of cancer beyond breast cancer, potentially improving therapy through targeting a specific phase of the cell cycle of cancer cells.

Central nervous system tumors are the leading cause of cancer related death in children. Despite much progress in the field of pediatric neurooncology, modern combination treatment regimens often result in significant late effects, such as neurocognitive deficits, endocrine dysfunction, secondary malignancies, and a host of other chronic health problems. Precision medicine strategies applied to pediatric neurooncology target specific characteristics of individual patients' tumors to achieve maximal killing of neoplastic cells while minimizing unwanted adverse effects. Here, we review emerging trends and the current literature that have guided the development of new molecularly based classification schemas, promising diagnostic techniques, targeted therapies, and delivery platforms for the treatment of pediatric central nervous system tumors.

Background: The mechanism of tumorigenicity potentially evolved in mesenchymal stem cells (MSCs) remains elusive, resulting in inconsistent clinical application efficacy. We hypothesized that subclones in MSCs contribute to their tumorgenicity, and we approached MSC-subclones at the single-cell level. Methods: MSCs were cultured in an osteogenic differentiation medium and harvested on days 12, 19, and 25 for cell differentiation analysis using Alizarin Red and followed with the single-cell transcriptome. Results: Single-cell RNA-seq analysis reveals a discrete cluster of MSCs during osteogenesis, including differentiation-resistant MSCs (DR-MSCs), differentiated osteoblasts (DO), and precursor osteoblasts (PO). The DR-MSCs population resembled cancer initiation cells and were subjected to further analysis of the yes associated protein 1 (YAP1) network. Verteporfin was also used for YAP1 inhibition in cancer cell lines to confirm the role of YAP1 in MSC--involved tumorigenicity. Clinical data from various cancer types were analyzed to reveal relationships among YAP1, OCT4, and CDH6 in MSC--involved tumorigenicity. The expression of cadherin 6 (CDH6), octamer-binding transcription factor 4 (OCT4), and YAP1 expression was significantly upregulated in DR-MSCs compared to PO and DO. YAP1 inhibition by Verteporfin accelerated the differentiation of MSCs and suppressed the expression of YAP1, CDH6, and OCT4. A survey of 56 clinical cohorts revealed a high degree of co-expression among CDH6, YAP1, and OCT4 in various solid tumors. YAP1 inhibition also down-regulated HeLa cell viability and gradually inhibited YAP1 nuclear localization while reducing the transcription of CDH6 and OCT4. Conclusions: We used single-cell sequencing to analyze undifferentiated MSCs and to discover a carcinogenic pathway in single-cell MSCs of differentiated resistance subclones.