The Development and Evaluation of a Patient Educational Resource for Cancer-Related Cognitive Dysfunction.

Cancer patients and survivors frequently experience cognitive deficits, including problems with attention and memory. These symptoms, referred to as cancer-related cognitive dysfunction (CRCD), are associated with distress. Learning about CRCD and self-management strategies may improve functioning and quality of life in cancer survivors. This study describes the development and evaluation of a CRCD resource for cancer patients. An educational booklet was developed in accordance with multiple evidence-based guidelines for cancer patient education. Cancer patients on chemotherapy (N = 113; 34% men; median age 55, range 19-85) reviewed the booklet and self-reported CRCD knowledge before and after reading the booklet. They also gave ratings on general impressions of the booklet. Seventy-five percent of participants reported that the resource increased their self-reported CRCD knowledge. A Wilcoxon signed-rank test demonstrated that exposure to the booklet elicited a statistically significant change in self-reported knowledge (Z = - 7.13, p < 0.001). A repeated-measures ANCOVA determined that the means of self-reported CRCD knowledge were significantly different between pre- and post-exposure (F(1, 92) = 7.96, p = 0.006, η2 = 0.08). Exploratory analyses revealed that self-reported CRCD knowledge increased across all educational attainment levels from pre- to post-exposure. Ninety-one percent of participants reported that all patients undergoing cancer treatment would find this booklet helpful. Cancer patients at risk for cognitive challenges gained self-reported CRCD knowledge from the booklet, and they think this knowledge would be helpful to others. A resource that makes CRCD understandable and manageable can bridge the gap in self-rated knowledge across education levels.

ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells.

Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers.

A tumorigenic MLL-homeobox network in human glioblastoma stem cells.

Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox gene HOXA10. In turn, HOXA10 activates a downstream Homeobox network and other genes previously characterized for their role in tumorigenesis. The MLL-Homeobox axis we identified significantly contributes to the tumorigenic potential of glioblastoma stem cells. Our studies suggest a role for MLL in contributing to the epigenetic heterogeneity between tumor-initiating and non-tumor-initiating cells in glioblastoma.

Multipotent CD15+ cancer stem cells in patched-1-deficient mouse medulloblastoma.

Subpopulations of tumorigenic cells have been identified in many human tumors, although these cells may not be very rare in some types of cancer. Here, we report that medulloblastomas arising from Patched-1-deficient mice contain a subpopulation of cells that show a neural precursor phenotype, clonogenic and multilineage differentiation capacity, activated Hedgehog signaling, wild-type Patched-1 expression, and the ability to initiate tumors following allogeneic orthotopic transplantation. The normal neural stem cell surface antigen CD15 enriches for the in vitro proliferative and in vivo tumorigenic potential from uncultured medulloblastomas, supporting the existence of a cancer stem cell hierarchy in this clinically relevant mouse model of cancer.

Chemical genetics reveals a complex functional ground state of neural stem cells.

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.