In studies of KPC mice with disruption of C1galt1, we found that loss of C1galt1 promotes development of aggressive PDACs and increased metastasis. Knockout of C1galt1 leads to increased tumorigenicity and truncation of O-glycosylation on MUC16, which could contribute to increased aggressiveness.

Introduction Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance. Area covered We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC. Expert opinion Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance,MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.

Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a metastatic niche and metabolic reprogramming via regulation of their target genes. However, the role of miRNA in breast cancer brain metastasis (BCBM) is poorly explored. Thus, identification and understanding of miRNAs in the pathobiology of BCBM may identify a novel candidate miRNA for the early diagnosis and prevention of this devastating process. In this review, we focus on understanding the role of candidate miRNAs in the regulation of BC brain metastatic processes as well as designing novel miRNA-based therapeutic strategies for BCBM.Keywords: Breast cancer brain metastasis, miRNA, Brain tumor microenvironment, Blood-brain barrier, CNS metastasis

Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR‐1253, a brain‐enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR‐1253 confers novel tumor‐suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR‐1253. We then explored the anti‐tumorigenic properties of miR‐1253, in parallel with a biochemical analysis of apoptosis and proliferation, and isolated oncogenic targets using high‐throughput screening. Deregulation of miR‐1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de‐methylation of miR‐1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest and reduction of markers of proliferation. We identified two oncogenic targets of miR‐1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR‐1253. These data reveal novel tumor‐suppressive properties for miR‐1253, i.e., (i) loss of expression via epigenetic silencing; (ii) negative trophic effects on tumor aggressiveness; and (iii) downregulation of oncogenic targets.

Afflicted neurons in Alzheimer disease have been shown to display an imbalance in the expression of TrkA and p75NTR at the cell surface, and administration of nerve growth factor (NGF) has been considered and attempted for treatment. However, wild-type NGF causes extensive elaboration of neurites while providing survival support. This study was aimed at developing recombinant NGF muteins that did not support neuritogenesis while maintaining the survival response. Critical residues were identified at the ligand-receptor interface by point mutagenesis that played a greater importance in neuritogenesis versus survival. By combining point mutations, two survival-selective recombinant NGF muteins, i.e./7-84-103 and KKE/7-84-103, were generated. Both muteins reduced neuritogenesis in PC12 (TrkA ؉ /p75 NTR؉ ) cells by >90%, while concurrently retaining near wild-type survival activity in MG139 (TrkA Neurotrophins are a family of closely related proteins that have diverse functions ranging from neuronal survival and differentiation to regulation of axonal and dendritic outgrowth, synapse formation, cell migration, and cellular proliferation (1-5). The family of neurotrophins was established with the discovery of its founding member, nerve growth factor (NGF) 3 (3, 6, 7). Brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) possess a high sequence homology (ϳ50%) and adopt similar tertiary structures (7-12). Neurotrophins bind selectively to a family of 140-kDa Tropomyosin-receptor-kinases (Trk), i.e. NGF to TrkA, brain-derived neurotrophic factor and NT-4 to TrkB, and NT-3 to TrkC, via interactions with a nanomolar affinity (K d ϳ10 Ϫ9 M) (13-16). All neurotrophins can also bind a 75-kDa common neurotrophin receptor, p75 NTR , via similar affinity interactions (17, 18).NGF is a target-derived polypeptide synthesized by the hippocampus and retrogradely transported within axons of cholinergic interneurons (striatum), magnocellular cholinergic neurons (basal forebrain), and Purkinje cells (cerebellum) (19 -22). NGF is secreted as a propeptide of 305 residues (ϳ35 kDa), pro-NGF, and subsequently cleaved at the N terminus by serine proteases to generate a smaller 120-amino acid mature polypeptide (ϳ13 kDa) (23,24). The folded monomer is stabilized by three disulfide bridges that form the core cystine-knot motif, characteristic of all neurotrophins (25,26). Each monomer is composed of two pairs of antiparallel ␤-strands connected by four ␤-hairpin loops (25). NGF possesses highly conserved hydrophobic residues along the elongated central axis of the molecule, which facilitates its tight association into a noncovalent homodimer (K d Ͻ10 Ϫ13 M) (25,27). The solvent-exposed ␤-hairpin loops (I-V), along with the N and C termini, are highly variable across neurotrophins and play a functional role in establishing specificity in receptor activation (12, 17, 26, 28 -31).The crystal structure of a symmetric complex of dimeric NGF bound to a pair of TrkA-d 5 domains identified two critical pat...