SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.

KRAS is the most commonly mutated oncogene. Targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance.

Androgen receptor inhibition suppresses anti-tumor neutrophil response against bone metastatic prostate cancer via regulation of TβRI expression.

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms.

Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy.

Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anticancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential.

Design, synthesis, and evaluation of a mitoxantrone probe (MXP) for biological studies.

Mitoxantrone (MX) is a robust chemotherapeutic with well-characterized applications in treating certain leukemias and advanced breast and prostate cancers. The canonical mechanism of action associated with MX is its ability to intercalate DNA and inhibit topoisomerase II, giving it the designation of a topoisomerase II poison. Years after FDA approval, investigations have unveiled novel protein-binding partners, such as methyl-CpG-binding domain protein (MBD2), PIM1 serine/threonine kinase, RAD52, and others that may contribute to the therapeutic profile of MX.

Coming of Age: Targeting Cyclin K in Cancers.

Cyclins and cyclin-dependent kinases (CDKs) play versatile roles in promoting the hallmarks of cancer. Therefore, cyclins and CDKs have been widely studied and targeted in cancer treatment, with four CDK4/6 inhibitors being approved by the FDA and many other inhibitors being examined in clinical trials. The specific purpose of this review is to delineate the role and therapeutic potential of Cyclin K in cancers.

Roles unveiled for membrane-associated mucins at the ocular surface using a Muc4 knockout mouse model.

Membrane-associated mucins (MAMs) are proposed to play critical roles at the ocular surface; however, in vivo evidence has been lacking. Here we investigate these roles by phenotyping of a Muc4 KO mouse. Histochemical analysis for expression of the beta-galactosidase transgene replacing Muc4 revealed a spiraling ribbon pattern across the corneal epithelium, consistent with centripetal cell migration from the limbus.

Luteal Lipid Droplets: A Novel Platform for Steroid Synthesis.

Progesterone is an essential steroid hormone that is required to initiate and maintain pregnancy in mammals and serves as a metabolic intermediate in the synthesis of endogenously produced steroids, including sex hormones and corticosteroids. Steroidogenic luteal cells of the corpus luteum have the tremendous capacity to synthesize progesterone. These specialized cells are highly enriched with lipid droplets that store lipid substrate, which can be used for the synthesis of steroids.

Interactome Profiling of DNA Damage Response (DDR) Mediators with Immunoprecipitation-Mass Spectrometry.

Immunoprecipitation-mass spectrometry (IP-MS) is a versatile tool to probe for global protein-protein interactions (PPIs) in biological samples. Such interactions coordinate complex biological processes, such as the DNA damage response (DDR). Induction of DNA damage activates signaling networks where posttranslational modifications cause PPI that facilitate DNA repair and cell cycle coordination.

Chimeric antibody targeting unique epitope on onco-mucin16 reduces tumor burden in pancreatic and lung malignancies.

Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers.

GPCRs and fibroblast heterogeneity in fibroblast-associated diseases.

G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of "most targeted receptors". About one-third of the commercially available drugs for various diseases target the GPCRs.

Ligand-installed polymeric nanocarriers for combination chemotherapy of EGFR-positive ovarian cancer.

Combination chemotherapeutic drugs administered via a single nanocarrier for cancer treatment provides benefits in reducing dose-limiting toxicities, improving the pharmacokinetic properties of the cargo and achieving spatial-temporal synchronization of drug exposure for maximized synergistic therapeutic effects. In an attempt to develop such a multi-drug carrier, our work focuses on functional multimodal polypeptide-based polymeric nanogels (NGs). Diblock copolymers poly (ethylene glycol)-b-poly (glutamic acid) (PEG-b-PGlu) modified with phenylalanine (Phe) were successfully synthesized and characterized.

USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma.

Unlabelled: In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most EWS, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress.

EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis.

Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD1 mRNA expression specifying shorter patient survival. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis.

The mutational landscape of a US Midwestern breast cancer cohort reveals subtype-specific cancer drivers and prognostic markers.

Background: Female breast cancer remains the second leading cause of cancer-related death in the USA. The heterogeneity in the tumor morphology across the cohort and within patients can lead to unpredictable therapy resistance, metastasis, and clinical outcome. Hence, supplementing classic pathological markers with intrinsic tumor molecular markers can help identify novel molecular subtypes and the discovery of actionable biomarkers.

Immunotherapy: an emerging modality to checkmate brain metastasis.

The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden.

A Novel HOXA10-Associated 5-Gene-Based Prognostic Signature for Stratification of Short-term Survivors of Pancreatic Ductal Adenocarcinoma.

Purpose: Despite the significant association of molecular subtypes with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), few efforts have been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes.

Experimental Design: We analyzed the transcriptomic profiles of treatment-naïve surgically resected short-term survivor (STS) and long-term survivor (LTS) tumors (GSE62452) for expression and survival, followed by validation in several datasets.

The role of catalytic and regulatory domains of human PrimPol in DNA binding and synthesis.

Human PrimPol possesses DNA primase and DNA polymerase activities and restarts stalled replication forks protecting cells against DNA damage in nuclei and mitochondria. The zinc-binding motif (ZnFn) of the C-terminal domain (CTD) of PrimPol is required for DNA primase activity but the mechanism is not clear. In this work, we biochemically demonstrate that PrimPol initiates de novo DNA synthesis in cis-orientation, when the N-terminal catalytic domain (NTD) and the CTD of the same molecule cooperate for substrates binding and catalysis.

Perfect Crystals: microgravity capillary counterdiffusion crystallization of human manganese superoxide dismutase for neutron crystallography.

The NASA mission Perfect Crystals used the microgravity environment on the International Space Station (ISS) to grow crystals of human manganese superoxide dismutase (MnSOD)-an oxidoreductase critical for mitochondrial vitality and human health. The mission's overarching aim is to perform neutron protein crystallography (NPC) on MnSOD to directly visualize proton positions and derive a chemical understanding of the concerted proton electron transfers performed by the enzyme. Large crystals that are perfect enough to diffract neutrons to sufficient resolution are essential for NPC.

Targeting the EGFR signaling pathway in cancer therapy: What's new in 2023?

Introduction: Epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, and mutated in multiple cancers. In normal cell physiology, EGFR signaling controls cellular differentiation, proliferation, growth, and survival. During tumorigenesis, mutations in EGFR lead to increased kinase activity supporting survival, uncontrolled proliferation, and migratory functions of cancer cells.

STAT3 Inhibition Attenuates MYC Expression by Modulating Co-Activator Recruitment and Suppresses Medulloblastoma Tumor Growth by Augmenting Cisplatin Efficacy In Vivo.

MB is a common childhood malignancy of the central nervous system, with significant morbidity and mortality. Among the four molecular subgroups, MYC-amplified Group 3 MB is the most aggressive type and has the worst prognosis due to therapy resistance. The present study aimed to investigate the role of activated STAT3 in promoting MB pathogenesis and chemoresistance via inducing the cancer hallmark MYC oncogene.

PTGES Expression Is Associated with Metabolic and Immune Reprogramming in Pancreatic Ductal Adenocarcinoma.

Metabolic reprogramming is an established hallmark of multiple cancers, including pancreatic cancer. Dysregulated metabolism is utilized by cancer cells for tumor progression, metastasis, immune microenvironment remodeling, and therapeutic resistance. Prostaglandin metabolites have been shown to be critical for inflammation and tumorigenesis.

Uncovering Tumor-Promoting Roles of Activin A in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high incidence rates of metastasis and cachexia. High circulating activin A, a homodimer of inhibin βA subunits that are encoded by INHBA gene, predicts poor survival among PDAC patients. However, it still raises the question of whether activin A suppression renders favorable PDAC outcomes.