👤 Michael P Diamond

Fibroblast growth factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urothelial carcinoma. Currently approved FGFR2/3-targeted therapies rely on pan-FGFR small-molecule kinase inhibitors, which often lead to off-target toxicities due to unintended inhibition of FGFR1 and FGFR4, as well as acquired resistance driven by gatekeeper mutations. Herein, we report the discovery of INCB126503, a highly potent, orally bioavailable FGFR2/3 inhibitor with excellent isoform selectivity and equipotent activity against gatekeeper mutants. INCB126503 effectively suppresses FGFR signaling in vivo without inducing hyperphosphatemia and demonstrates significant antitumor efficacy in xenograft models harboring FGFR3 genetic alterations. Show less

Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity. Show less

Transcellular propagation of protein aggregate "seeds" has been proposed to mediate the progression of neurodegenerative diseases in tauopathies and α-synucleinopathies. We previously reported that tau and α-synuclein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface, promoting cellular uptake and intracellular seeding. However, the specificity and binding mode of these protein aggregates to HSPGs remain unknown. Here, we measured direct interaction with modified heparins to determine the size and sulfation requirements for tau, α-synuclein, and β-amyloid (Aβ) aggregate binding to glycosaminoglycans (GAGs). Varying the GAG length and sulfation patterns, we next conducted competition studies with heparin derivatives in cell-based assays. Tau aggregates required a precise GAG architecture with defined sulfate moieties in the Show less

While chromosome 1 is the largest chromosome in the human genome, less than two dozen cases of interstitial microdeletions in the short arm have been documented. More than half of the 1p microdeletion cases were reported in the pre-microarray era and as a result, the proximal and distal boundaries containing the exact number of genes involved in the microdeletions have not been clearly defined. We revisited a previous case of a 10-year old female patient with a 1p32.1p32.3 microdeletion displaying syndromic intellectual disability. We performed microarray analysis as well as qPCR to define the proximal and distal deletion breakpoints and revised the karyotype from 1p32.1p32.3 to 1p31.3p32.2. The deleted chromosomal region contains at least 35 genes including NFIA. Comparative deletion mapping shows that this region can be dissected into five chromosomal segments containing at least six candidate genes (DAB1, HOOK1, NFIA, DOCK7, DNAJC6, and PDE4B) most likely responsible for syndromic intellectual disability, which was corroborated by their reduced transcript levels in RT-qPCR. Importantly, one patient with an intragenic microdeletion within NFIA and an additional patient with a balanced translocation disrupting NFIA display intellectual disability coupled with macrocephaly. We propose NFIA is responsible for intellectual disability coupled with macrocephaly, and microdeletions at 1p31.3p32.2 constitute a contiguous gene syndrome with several genes contributing to syndromic intellectual disability. Show less

The genetic etiology of sporadic neuroblastoma is still largely obscure. In a genome-wide association study, we identified single-nucleotide polymorphisms (SNP) associated with neuroblastoma at the CASC15, BARD1, LMO1, DUSP12, HSD17B12, HACE1, and LIN28B gene loci, but these explain only a small fraction of neuroblastoma heritability. Other neuroblastoma susceptibility genes are likely hidden among signals discarded by the multiple testing corrections. In this study, we evaluated eight additional genes selected as candidates for further study based on proven involvement in neuroblastoma differentiation. SNPs at these candidate genes were tested for association with disease susceptibility in 2,101 cases and 4,202 controls, with the associations found replicated in an independent cohort of 459 cases and 809 controls. Replicated associations were further studied for cis-effect using gene expression, transient overexpression, silencing, and cellular differentiation assays. The neurofilament gene NEFL harbored three SNPs associated with neuroblastoma (rs11994014: Pcombined = 0.0050; OR, 0.88; rs2979704: Pcombined = 0.0072; OR, 0.87; rs1059111: Pcombined = 0.0049; OR, 0.86). The protective allele of rs1059111 correlated with increased NEFL expression. Biologic investigations showed that ectopic overexpression of NEFL inhibited cell growth specifically in neuroblastoma cells carrying the protective allele. NEFL overexpression also enhanced differentiation and impaired the proliferation and anchorage-independent growth of cells with protective allele and basal NEFL expression, while impairing invasiveness and proliferation of cells homozygous for the risk genotype. Clinically, high levels of NEFL expression in primary neuroblastoma specimens were associated with better overall survival (P = 0.03; HR, 0.68). Our results show that common variants of NEFL influence neuroblastoma susceptibility and they establish that NEFL expression influences disease initiation and progression. Show less

Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells to trigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we find that tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neurons by heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1. Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellular aggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocks neuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils, but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifying mechanism of cell uptake and propagation for tauopathy and synucleinopathy. Show less

Neuroblastoma is a malignant neoplasm of the developing sympathetic nervous system that is notable for its phenotypic diversity. High-risk patients typically have widely disseminated disease at diagnosis and a poor survival probability, but low-risk patients frequently have localized tumors that are almost always cured with little or no chemotherapy. Our genome-wide association study (GWAS) has identified common variants within FLJ22536, BARD1, and LMO1 as significantly associated with neuroblastoma and more robustly associated with high-risk disease. Here we show that a GWAS focused on low-risk cases identified SNPs within DUSP12 at 1q23.3 (P = 2.07 × 10⁻⁶), DDX4 and IL31RA both at 5q11.2 (P = 2.94 × 10⁻⁶ and 6.54 × 10⁻⁷ respectively), and HSD17B12 at 11p11.2 (P = 4.20 × 10⁻⁷) as being associated with the less aggressive form of the disease. These data demonstrate the importance of robust phenotypic data in GWAS analyses and identify additional susceptibility variants for neuroblastoma. Show less