Biology subjects

Finch, A. J.

Publications and source records attributed to Finch, A. J..

6 recordsLinked to original sources

bioRxiv2025

Human brown adipose tissue demonstrates substantial 18F-fluorocholine uptake at room temperature for phosphatidylcholine synthesis

ObjectiveBrown Adipose Tissue (BAT) is composed of mitochondrial-rich, multilocular adipocytes, which dissipate energy to produce heat. Quantification of BAT mass is most commonly performed by 18F-fluorodeoxyglucose positron emission tomography (PET), which requires antecedent cold exposure. We hypothesized that 18F-fluorocholine PET could detect human BAT due to its requirement for considerable phosphatidylcholine synthesis, secondary to brown adipocytes high mitochondrial density and multiple lipid droplets. Methods1) Six healthy men with detectable 18F-fluorodeoxyglucose uptake by BAT were recruited to a randomised crossover study investigating 18F-fluorocholine uptake by BAT during warm and cold exposure. 2) 18F-fluorocholine uptake by supraclavicular adipose tissue was quantified in 76 patients who had undergone 18F-fluorocholine PET/CT scanning. 3) Choline transporter expression was quantified in human BAT and white adipose tissue (WAT), and in brown and white adipocytes. 4) Lipidomics was performed on human brown adipocytes incubated with 15N-choline to determine phospholipid synthesis. Results1) 18F-Fluorocholine uptake by BAT was substantially greater than by WAT during both warm and cold exposure. 2) 18F-Fluorocholine uptake by supraclavicular adipose tissue was higher in the colder seasons, inversely associated with body mass index, and positively associated with tissue radiodensity. 3) Expression of the choline transporter SLC44A3 was higher in human supraclavicular BAT than WAT, while SLC44A2 was expressed more highly in human brown than white adipocytes. 4) 15N-choline tracing in human brown adipocytes identified incorporation into >30 phosphatidylcholine species. Conclusions18F-fluorocholine PET may be a novel method to quantify human BAT at room temperature. HighlightsO_LI18F-Fluorocholine (FCH) PET can detect human BAT without the need for cold exposure. C_LIO_LI18F-FCH uptake by supraclavicular AT is inversely associated with body mass index. C_LIO_LIThe choline transporter SLC44A3 is more highly expressed in BAT than WAT. C_LIO_LIHuman brown adipocytes utilise choline for phosphatidylcholine synthesis. C_LI O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/671970v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@11e85forg.highwire.dtl.DTLVardef@1aec87forg.highwire.dtl.DTLVardef@1ed3bf3org.highwire.dtl.DTLVardef@1fadbd1_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

physiology↗

bioRxiv2025

LIMD1 Loss Confers a GPX4-Dependent Cell State in Lung Cancer

LIMD1 (LIM domains containing 1) is a bona-fide tumour suppressor gene frequently lost during the early stages of non-small cell lung cancer (NSCLC) development, resulting in a worse outcome for LIMD1-deficient patients. LIMD1 deficiency is present in approximately 50% of NSCLC cases, representing at least 21,000 patients in the United Kingdom and 1.2 million worldwide. During cancer progression, cells can accumulate genetic changes that render them more dependent on certain genes for their survival. By performing CRISPR-Cas9 dropout screens, we identified GPX4 as a novel vulnerability in LIMD1 deficient LUAD cells. By targeting GPX4 using RNA interference (RNAi) and pharmacological intervention in our isogenic LUAD lines along with a non-transformed lung cell line, we validated GPX4 as a novel dependency in LIMD1 deficient cells. GPX4 is a key defence mechanism against ferroptosis, an iron-dependent form of regulated cell death. This state of increased ferroptosis susceptibility upon LIMD1 loss is due to increased basal reactive oxygen species levels and lipid peroxidation. Importantly, targeting GPX4 with ferroptosis inducing agents in NSCLC patients with LIMD1 loss may represent a novel therapeutic strategy.

cancer biology↗

bioRxiv2023

SCD inhibition eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy

Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients outcome. These features should be ideally present in many patients independently of mutational background. Here we identify de novo fatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML models in vitro and in vivo. We use the novel clinical grade SCD inhibitor SSI-4 to show that SCD inhibition induces AML cell death via pleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. SSI-4 efficacy is enhanced by driving FA biosynthesis in vitro while stroma confers protective effects that extend to in vivo models. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their therapeutic potential. One Sentence SummarySCD inhibition is toxic to AML cells with high rates of fatty acid desaturation and in combination with chemotherapy prolongs survival in murine AML models.

cancer biology↗

bioRxiv2019

De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

The aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CGIs are targeted by de novo DNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels of de novo DNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that instead de novo DNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

genetics↗

bioRxiv2018

The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype.

Cellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

cell biology↗

bioRxiv2018

ITPase Deficiency Causes Martsolf Syndrome With a Lethal Infantile Dilated Cardiomyopathy

Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Through genetic analysis of 85 unrelated \"mutation negative\" probands referred with Martsolf syndrome we identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). The probands reported here each presented with a lethal and highly distinctive disorder; Martsolf syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rl/dl) into RNA and DNA. In Itpa-null cells, dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA but this was not associated with detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in lymphoblastoid RNA from an affected individual. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA - and by implication rI production - correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.\n\nAuthor SummaryNucleotide triphosphate bases containing inosine, ITP and dITP, are continually produced within the cell as a consequence of various essential biosynthetic reactions. The enzyme inosine triphosphate pyrophosphatase (ITPase) scavenges ITP and dITP to prevent their incorporation into RNA and DNA. Here we describe two unrelated families with complete loss of ITPase function as a consequence of disruptive mutations affecting both alleles of ITPA, the gene that encodes this protein. Both of the families have a very distinctive and severe combination of clinical problems, most notably a failure of heart muscle that was lethal in infancy or early childhood. They also have features of another rare genetic disorder affecting the brain and the eyes called Martsolf syndrome. We could not detect any evidence of dITP accumulation in genomic DNA from the affected individuals. A low but detectable level of inosine was present in the mitochondrial DNA but this did not have any obvious detrimental effect. The inosine accumulation in RNA was detectable in the patient cells. We made both cellular and animal models that were completely deficient in ITPase. Using these reagents we could show that the highest level of inosine accumulation into RNA was seen in the embryonic mouse heart. In this tissue more than 1 in 400 bases in all RNA in the cell was inosine. In normal tissues inosine is almost undetectable using very sensitive assays. The inosine accumulation did not seem to be having a global effect on the balance of RNA molecules or proteins.

genetics↗