Oncogenic potential of truncated-Gli3 via the Gsk3β/Gli3/AR-V7 axis in castration-resistant prostate cancer.

The functional activation of the androgen receptor (AR) and its interplay with the aberrant Hh/Gli cascade are pivotal in the progression of castration-resistant prostate cancer (CRPC) and resistance to AR-targeted therapies. Our study unveiled a novel role of the truncated form of Gli (t-Gli3) in advancing CRPC. Investigation into Gli3 regulation revealed a Smo-independent mechanism for its activation.

Immunogenic Cell Death Traits Emitted from Chronic Lymphocytic Leukemia Cells Following Treatment with a Novel Anti-Cancer Agent, SpiD3.

Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies.

Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors.

Antibody-drug conjugates (ADCs) are increasingly used in clinic for multiple indications and may improve upon the activity of parental antibodies by delivering cytotoxic payloads into target cells. This activity is predicated upon internalization to release the cytotoxic payloads intracellularly. Since binding of ADCs to their cell surface targets does not guarantee their internalization, we hypothesize that proteolysis targeting chimeras (PROTACs) could improve the activity of ADCs through forced internalization.

Enoki-Inspired Microfibers and Extracellular Matrix Enhance Biaxially Interlocking Interfaces.

Taking inspiration from diverse interlocking and adhesion structures found in nature, a biaxially interlocking interface is developed in this work. This interface is formed by interconnecting two electrostatically flocked substrates and its mechanical strength is enhanced through the incorporation of enoki mushroom-shaped microfibers and deposited extracellular matrix (ECM). Tips of flocked straight fibers can be transformed into mushroom shapes through thermal treatment.

Elevated Expression of Cell Adhesion, Metabolic, and Mucus Secretion Gene Clusters Associated with Tumorigenesis, Metastasis, and Poor Survival in Pancreatic Ductal Adenocarcinoma.

Objectives: Technological advances in identifying gene expression profiles are being applied to study an array of cancers. The goal of this study was to identify differentially expressed genes in pancreatic ductal adenocarcinoma (PDAC) and examine their potential role in tumorigenesis and metastasis.

Methods: The transcriptomic profiles of PDAC and non-tumorous tissue samples were derived from the gene expression omnibus (GEO), which is a public repository.

Coxsackievirus and adenovirus receptor expression facilitates enteroviral infections to drive the development of pancreatic cancer.

The development of pancreatic cancer requires both, acquisition of an oncogenic mutation in KRAS as well as an inflammatory insult. However, the physiological causes for pancreatic inflammation are less defined. We show here that oncogenic KRas-expressing pre-neoplastic lesion cells upregulate coxsackievirus (CVB) and adenovirus receptor (CAR).

Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer.

Background: Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach - leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) - can minimize off-target toxicity related to TAT, often associated with full-length antibodies.

PAF1-mediated transcriptional reprogramming confers docetaxel resistance in advanced prostate cancer.

Advanced prostate cancer (PCa) remains a significant clinical challenge, and docetaxel plays a significant role in disease management. Despite the efficacy of docetaxel as a first-line chemotherapy, resistance often develops. We developed three clinically relevant in vitro PCa cell models and transcriptomic analysis identified that the Paf1/RNA polymerase II complex component (PAF1)-associated pluripotent-transcription factor (TF), SOX2, plays a crucial role in docetaxel resistance.

SART1 modulates poly-(ADP-ribose) chain accumulation and PARP1 chromatin localization.

PARP1 inhibitors (PARPis) are used for treatment of cancers with mutations in or that are deficient in homologous recombination. The identification of modulators of PARP1 activity is critical to understand and overcome resistance to PARPis. We integrated data from three omics-scale screens to discover new regulators of PARP1 activity.

Single-cell RNA-sequencing of human spleens reveals an IDO-1 tolerogenic dendritic cell subset in pancreatic cancer patients that is absent in normal individuals.

Local and systemic immunosuppression are prominent features of pancreatic cancer, rendering anti-tumor effector cells inactive and immunotherapeutic approaches ineffective. The spleen, an understudied point of antigen-presentation and T cell priming in humans, holds particular importance in pancreatic cancer due to its proximity to the developing tumor. As main effectors of antigen presentation, dendritic cells display antigens to lymphocytes, thereby bridging the innate and adaptive immune response.

Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases.

Oncogenic mutations in the gene are detected in >90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC.

Pharmacokinetics and fate of free and encapsulated IRD800CW-labelled human BChE intravenously administered in mice.

Human butyrylcholinesterase (BChE) is an efficient bioscavenger of toxicants. Highly purified BChE was labelled with the near infrared fluorescent IRDye800CW. The goal was to determine the pharmacokinetics and fate of enzyme in mice.

Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence.

Glioblastoma (GBM) is an incurable disease with high intratumoral heterogeneity. Bioinformatic studies have examined transcriptional heterogeneity with differing conclusions. Here, we characterize GBM heterogeneity and highlight critical phenotypic and hierarchical roles for quiescent cancer stem cells (qCSCs).

Global screening of base excision repair in nucleosome core particles.

DNA damage is a fundamental molecular cause of genomic instability. Base excision repair (BER) is one line of defense to minimize the potential mutagenicity and/or toxicity derived from damaged nucleobase lesions. However, BER in the context of chromatin, in which eukaryotic genomic DNA is compacted through a hierarchy of DNA-histone protein interactions, is not fully understood.

Sugar symphony: glycosylation in cancer metabolism and stemness.

Glycosylation is a complex co-translational and post-translational modification (PTM) in eukaryotes that utilizes glycosyltransferases to generate a vast array of glycoconjugate structures. Recent studies have highlighted the role of glycans in regulating essential molecular, cellular, tissue, organ, and systemic biological processes with significant implications for human diseases, particularly cancer. The metabolic reliance of cancer, spanning tumor initiation, disease progression, and resistance to therapy, necessitates a range of uniquely altered cellular metabolic pathways.

MUC16 Retention after Neoadjuvant Chemotherapy in Pancreatic Ductal Adenocarcinoma.

: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Currently, surgical resection is the only potentially curative treatment. Unfortunately, less than 20% of PDAC patients are eligible for surgical resection at diagnosis.

The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax.

Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.

Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function.

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting.

SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma.

The clinical effectiveness of KRASG12C inhibitors (G12Ci) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. Here, we identified targeting proximal receptor tyrosine kinase signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment. SOS1i enhanced the efficacy of G12Ci and limited rebound receptor tyrosine kinase/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels.

Protein Structure Inspired Discovery of a Novel Inducer of Anoikis in Human Melanoma.

Drug discovery historically starts with an established function, either that of compounds or proteins. This can hamper discovery of novel therapeutics. As structure determines function, we hypothesized that unique 3D protein structures constitute primary data that can inform novel discovery.

Targeted BET inhibition with OPN-51107 synergizes with venetoclax in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) remains incurable and its ability to acquire resistance to front-line therapeutics has proved challenging. Bromodomain and extra-terminal proteins, particularly bromodomain-containing protein 4 (BRD4), are integral to gene expression in CLL and offer a promising therapeutic target. In this study, we examined the activity of the BRD4 inhibitor OPN-51107 alone and in combination with the BCL-2 inhibitor, venetoclax, in CLL cell lines and patient-derived CLL samples.

Collapsed State Mediates the Low Fidelity of the DNA Polymerase β I260 Mutant.

DNA polymerase β (Pol β) fills single nucleotide gaps during base excision repair. Deficiencies in Pol β can lead to increased mutagenesis and genomic instability in the cell, resulting in cancer. Our laboratory has previously shown that the I260 M somatic mutation of Pol β, which was first identified in prostate cancer, has reduced nucleotide discrimination in a sequence context-dependent manner.