Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma.

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.

Histone demethylase KDM5D upregulation drives sex differences in colon cancer.

Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular and genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones1. Such sex differences are particularly prominent in colorectal cancer (CRC) in which men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumour suppressors (designated iKAP)2, revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and major histocompatibility complex class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells showed an increased propensity for more invasive tumours in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes substantially to the sex differences in KRAS* CRC by means of its disruption of cancer cell adhesion properties and tumour immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.

Ultra-sensitive and resilient compliant strain gauges for soft machines.

Soft machines are a promising design paradigm for human-centric devices1,2 and systems required to interact gently with their environment3,4. To enable soft machines to respond intelligently to their surroundings, compliant sensory feedback mechanisms are needed. Specifically, soft alternatives to strain gauges-with high resolution at low strain (less than 5 per cent)-could unlock promising new capabilities in soft systems. However, currently available sensing mechanisms typically possess either high strain sensitivity or high mechanical resilience, but not both. The scarcity of resilient and compliant ultra-sensitive sensing mechanisms has confined their operation to laboratory settings, inhibiting their widespread deployment. Here we present a versatile and compliant transduction mechanism for high-sensitivity strain detection with high mechanical resilience, based on strain-mediated contact in anisotropically resistive structures (SCARS). The mechanism relies upon changes in Ohmic contact between stiff, micro-structured, anisotropically conductive meanders encapsulated by stretchable films. The mechanism achieves high sensitivity, with gauge factors greater than 85,000, while being adaptable for use with high-strength conductors, thus producing sensors resilient to adverse loading conditions. The sensing mechanism also exhibits high linearity, as well as insensitivity to bending and twisting deformations-features that are important for soft device applications. To demonstrate the potential impact of our technology, we construct a sensor-integrated, lightweight, textile-based arm sleeve that can recognize gestures without encumbering the hand. We demonstrate predictive tracking and classification of discrete gestures and continuous hand motions via detection of small muscle movements in the arm. The sleeve demonstration shows the potential of the SCARS technology for the development of unobtrusive, wearable biomechanical feedback systems and human-computer interfaces.

Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Biocompatible Soft Fluidic Strain and Force Sensors for Wearable Devices.

Fluidic soft sensors have been widely used in wearable devices for human motion capturing. However, thus far, the biocompatibility of the conductive liquid, the linearity of the sensing signal, and the hysteresis between the loading and release processes have limited the sensing quality as well as the applications of these sensors. In this paper, silicone based strain and force sensors composed of a novel biocompatible conductive liquid (potassium iodide and glycerol solution) are introduced. The strain sensors exhibit negligible hysteresis up to 5 Hz, with a gauge factor of 2.2 at 1 Hz. The force sensors feature a novel multi-functional layered structure, with micro-cylinder-filled channels to achieve high linearity, low hysteresis (5.3% hysteresis at 1 Hz), and good sensitivity (100% resistance increase at a 5 N load). The sensors' gauge factors are stable at various temperatures and humidity levels. These bio-compatible, low hysteresis, and high linearity sensors are promising for safe and reliable diagnostic devices, wearable motion capture, and compliant human-computer interfaces.

Bistable cholesteric liquid crystal light shutter with multielectrode driving.

An electrically activated bistable light shutter that exploits polymer-stabilized cholesteric liquid crystal film was developed. Under double-sided three-terminal electrode driving, the device can be bistable and switched between focal conic and homeotropic textures with a uniform in-plane and vertical electrical field. The transparent state with a transmittance of 80% and the opaque/scattering state with a transmittance of 13% can be realized without any optical compensation film, and each can be simply switched to the other by applying a pulse voltage. Also, gray-scale selection can be performed by varying the applied voltage. The designed energy-saving bistable light shutter can be utilized to preserve privacy and control illumination and the flow of energy.

Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model.

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.

GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.

Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.

Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3ß inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.

LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.

Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma.

Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hallmark, as a potential basis underlying CLOCK's pro-tumor effect in GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results in hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN). As a result, secreted POSTN promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. In GBM mouse and patient-derived xenograft models, blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis. Thus, the CLOCK-POSTN-TBK1 circuit coordinates a key tumor-endothelial cell interaction and represents an actionable therapeutic target for GBM.

Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven colorectal cancer. SIGNIFICANCE: This study identified a molecular mechanism contributing to KRAS*-driven colorectal cancer progression via fibroblast transformation in the tumor microenvironment to produce VEGFA driving tumor angiogenesis. In preclinical models, targeting the KRAS*-TFCP2-VEGFA axis impaired tumor progression, revealing a potential novel therapeutic option for patients with KRAS*-driven colorectal cancer. This article is featured in Selected Articles from This Issue, p. 2489.

Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism.

Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as an induced vulnerability to therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.

A Comparison of McGrath Videolaryngoscope versus Macintosh Laryngoscope for Nasotracheal Intubation: A Systematic Review and Meta-Analysis.

BACKGROUND: In this study, it was shown that the routine use of McGrath videolaryngoscopy may improve intubation success rates. The benefits to using a videolaryngoscope in nasotracheal intubation were also demonstrated. However, no solid evidence concerning the effectiveness of the use of McGrath videolaryngoscopes in nasotracheal intubation has previously been reported. As a result, we questioned whether, in adult patients who underwent oral and maxillofacial surgeries with nasotracheal intubation (P), the use of a McGrath videolaryngoscope (I) compared with a Macintosh laryngoscope (C) could reduce the intubation time, improve glottis visualization to a score of classification 1 in the Cormack-Lehane classification system, and improve the first-attempt success rate (O). The secondary outcomes measured were the rate of the use of Magill forceps and the external laryngeal pressure (BURP) maneuver used. METHODS: An extensive literature search was conducted using databases. Only randomized controlled trials that compared the McGrath videolaryngoscopy and Macintosh laryngoscopy techniques in nasotracheal intubation in adult patients were included. RESULTS: Five articles met the inclusion criteria and were included in the final analysis (n = 331 patients). The results showed a significant decrease in intubation time and a higher rate of classification 1 scores in the Cormack-Lehane classification system, but no difference in the first-attempt success rates were found between the McGrath group and the Macintosh group. Decreases in the rate of the use of Magill forceps and the use of the external laryngeal pressure maneuver were also found in the pooled analysis. With regard to the overall risk of bias, the selected trials were classified to have at least a moderate risk of bias, because none of the trials could blind the operator to the type of laryngoscope used. CONCLUSIONS: Our analysis suggests that the use of a McGrath videolaryngoscope in nasotracheal intubation resulted in shorter intubation times, improved views of the glottis and similar first-success rates in adult patients who received general anesthesia for dental, oral, maxillofacial, or head and neck cancer surgery, and also reduced the use of Magill forceps and the BURP maneuver.

Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma.

The symbiotic interactions between cancer stem cells and the tumor microenvironment (TME) are critical for tumor progression. However, the molecular mechanism underlying this symbiosis in glioblastoma (GBM) remains enigmatic. Here, we show that circadian locomotor output cycles kaput (CLOCK) and its heterodimeric partner brain and muscle ARNT-like 1 (BMAL1) in glioma stem cells (GSC) drive immunosuppression in GBM. Integrated analyses of the data from transcriptome profiling, single-cell RNA sequencing, and TCGA datasets, coupled with functional studies, identified legumain (LGMN) as a direct transcriptional target of the CLOCK-BMAL1 complex in GSCs. Moreover, CLOCK-directed olfactomedin-like 3 (OLFML3) upregulates LGMN in GSCs via hypoxia-inducible factor 1-alpha (HIF1α) signaling. Consequently, LGMN promotes microglial infiltration into the GBM TME via upregulating CD162 and polarizes infiltrating microglia toward an immune-suppressive phenotype. In GBM mouse models, inhibition of the CLOCK-OLFML3-HIF1α-LGMN-CD162 axis reduces intratumoral immune-suppressive microglia, increases CD8+ T-cell infiltration, activation, and cytotoxicity, and synergizes with anti-programmed cell death protein 1 (anti-PD-1 therapy). In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial abundance and poor prognosis. Together, these findings uncover the CLOCK-OLFML3-HIF1α-LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for patients with GBM.

Synthetic Essentiality of Tryptophan 2,3-Dioxygenase 2 in APC-Mutated Colorectal Cancer.

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/ß-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient colorectal cancer models were susceptible to TDO2 depletion or pharmacologic inhibition, which impaired cancer cell proliferation and enhanced antitumor immune profiles. Thus, APC deficiency activates a TCF4-TDO2-AhR-CXCL5 circuit that affects multiple cancer hallmarks via autonomous and nonautonomous mechanisms and illuminates a genotype-specific vulnerability in colorectal cancer. SIGNIFICANCE: This study identifies critical effectors in the maintenance of APC-deficient colorectal cancer and demonstrates the relationship between APC/WNT pathway and kynurenine pathway signaling. It further determines the tumor-associated macrophage biology in APC-deficient colorectal cancer, informing genotype-specific therapeutic targets and the use of TDO2 inhibitors. This article is highlighted in the In This Issue feature, p. 1599.

ATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Cancer Stemness Meets Immunity: From Mechanism to Therapy.

Cancer stem cells (CSCs) are self-renewing cells that facilitate tumor initiation, promote metastasis, and enhance cancer therapy resistance. Transcriptomic analyses across many cancer types have revealed a prominent association between stemness and immune signatures, potentially implying a biological interaction between such hallmark features of cancer. Emerging experimental evidence has substantiated the influence of CSCs on immune cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and T cells, in the tumor microenvironment and, reciprocally, the importance of such immune cells in sustaining CSC stemness and its survival niche. This review covers the cellular and molecular mechanisms underlying the symbiotic interactions between CSCs and immune cells and how such heterotypic signaling maintains a tumor-promoting ecosystem and informs therapeutic strategies intercepting this co-dependency.

Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models.

Amyloid-induced neurodegeneration plays a central role in Alzheimer's disease (AD) pathogenesis. Here, we show that telomerase reverse transcriptase (TERT) haploinsufficiency decreases BDNF and increases amyloid-ß (Aß) precursor in murine brain. Moreover, prior to disease onset, the TERT locus sustains accumulation of repressive epigenetic marks in murine and human AD neurons, implicating TERT repression in amyloid-induced neurodegeneration. To test the impact of sustained TERT expression on AD pathobiology, AD mouse models were engineered to maintain physiological levels of TERT in adult neurons, resulting in reduced Aß accumulation, improved spine morphology, and preserved cognitive function. Mechanistically, integrated profiling revealed that TERT interacts with ß-catenin and RNA polymerase II at gene promoters and upregulates gene networks governing synaptic signaling and learning processes. These TERT-directed transcriptional activities do not require its catalytic activity nor telomerase RNA. These findings provide genetic proof-of-concept for somatic TERT gene activation therapy in attenuating AD progression including cognitive decline.