miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key posttranscriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown.

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment.

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females.

Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth.

Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity.

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown.

Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses.

Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator () gene, which encodes the homeostatic iron regulatory protein. While is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear.

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment.

Metaorganismal choline metabolism shapes olfactory perception.

Microbes living in the intestine can regulate key signaling processes in the central nervous system that directly impact brain health. This gut-brain signaling axis is partially mediated by microbe-host-dependent immune regulation, gut-innervating neuronal communication, and endocrine-like small molecule metabolites that originate from bacteria to ultimately cross the blood-brain barrier. Given the mounting evidence of gut-brain crosstalk, a new therapeutic approach of "psychobiotics" has emerged, whereby strategies designed to primarily modify the gut microbiome have been shown to improve mental health or slow neurodegenerative diseases.

Let the Guard Down: cAMP Activators Can Improve Immunotherapy in GBM.

Enhancing T-cell infiltration into glioblastoma (GBM) tumors has proven challenging yet remains crucial for improving the efficacy of immunotherapy for patients with this deadly cancer. In this issue, Qin, Huang, Li, and colleagues find that inhibiting vasculature formation driven by cancer stem cells is a promising target to enhance immunotherapy in GBM. See related article by Qin, Huang, Li, et al.

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Unlabelled: Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences.

GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.

The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor.

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population.

Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.

Unlabelled: In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared with granulocytic (g) MDSCs has yet to be determined.

Sex Differences in Glioblastoma Immunotherapy Response.

Glioblastoma (GBM), the most common primary malignant brain tumor, remains difficult to treat and shares phenotypes, including an aberrant immune response, with other neurological disorders. Understanding the cellular and molecular mechanisms underlying this pathological immune response remains a priority, particularly as standard of care for advanced cancers evolves to include immunotherapies, which have yet to show strong clinical efficacy in GBM. Epidemiological evidence supports a sex difference in GBM, with increased prevalence in males, and recent studies identified differences between males and females ranging from genetic aberrations to cellular programs.

A subset of broadly responsive Type III taste cells contribute to the detection of bitter, sweet and umami stimuli.

Taste receptor cells use multiple signaling pathways to detect chemicals in potential food items. These cells are functionally grouped into different types: Type I cells act as support cells and have glial-like properties; Type II cells detect bitter, sweet, and umami taste stimuli; and Type III cells detect sour and salty stimuli. We have identified a new population of taste cells that are broadly tuned to multiple taste stimuli including bitter, sweet, sour, and umami.

Temperature Is Sufficient to Condition a Flavor Preference for a Cold-Paired Solution in Rats.

Increasing evidence suggests that stimulus temperature modifies taste signaling. However, understanding how temperature modifies taste-driven behavior is difficult to separate as we must first understand how temperature alone modifies behavior. Previous work has suggested that cold water is more rewarding and "satiating" than warm water, and water above orolingual temperature is avoided in brief-access testing.

Altering salivary protein profile can decrease aversive oromotor responding to quinine in rats.

Bitter taste is often associated with toxins, but accepting some bitter foods, such as green vegetables, can be an important part of maintaining a healthy diet. It has previously been shown that animals exposed to quinine upregulate a set of salivary proteins (SPs), and those with upregulated SPs have increased rates of feeding on a quinine diet as well as increased brief-access licking to and higher detection thresholds for quinine. These studies suggest that SPs alter orosensory feedback; however, they rely on SPs upregulated by diet exposure and cannot control for the role of learning.

Rats are unable to discriminate quinine from diverse bitter stimuli.

Compounds described by humans as "bitter" are sensed by a family of type 2 taste receptors (T2Rs). Previous work suggested that diverse bitter stimuli activate distinct receptors, which might allow for perceptually distinct tastes. Alternatively, it has been shown that multiple T2Rs are expressed on the same taste cell, leading to the contrary suggestion that these stimuli produce a unitary perception.

Bitter-Induced Salivary Proteins Increase Detection Threshold of Quinine, But Not Sucrose.

Exposures to dietary tannic acid (TA, 3%) and quinine (0.375%) upregulate partially overlapping sets of salivary proteins which are concurrent with changes in taste-driven behaviors, such as rate of feeding and brief access licking to quinine. In addition, the presence of salivary proteins reduces chorda tympani responding to quinine.

Altering salivary protein profile can increase acceptance of a novel bitter diet.

Bitter taste is often associated with toxins, but accepting some bitter foods, such as green vegetables, can be an important part of maintaining a healthy diet. In rats and humans, repeated exposure to a bitter stimulus increases acceptance. Repeated exposure allows an individual the opportunity to learn about the food's orosensory and postingestive effects.

Salivary proteins alter taste-guided behaviors and taste nerve signaling in rat.

Taste stimuli are normally dissolved in saliva prior to interacting with their respective receptor targets. There are hundreds of proteins in saliva, and it has been hypothesized that these proteins could interact with either taste stimuli or taste receptors to alter taste signaling and diet acceptance. However, the impact of these proteins on feeding has been relatively unexplored using rodent models.