Biology subjects

Boyle, K.

Publications and source records attributed to Boyle, K..

4 recordsLinked to original sources

bioRxiv2026

Targeting REV7 exposes a mitotic vulnerability in colorectal cancer cells

Therapeutic resistance remains a barrier to durable treatment of colorectal cancer (CRC), highlighting the need to identify vulnerabilities in resistant tumor cells. REV7 (MAD2L2) is a multifunctional genome-maintenance protein with established roles in REV3-dependent translesion synthesis (TLS) as well as mitotic progression, spindle organization, and chromosome segregation. Although perturbing REV7 dependent DNA damage tolerance has emerged as a strategy to overcome chemoresistance, whether pharmacologic targeting of REV7 exposes vulnerabilities to mitotic disruption remains poorly understood. Here, we investigated the REV7 targeting small molecule inhibitor C10, which disrupts the REV7 and REV3 interaction, and found that C10 sensitized HCT116 and HT29 CRC cells to the microtubule-disrupting agent colchicine, resulting in markedly reduced clonogenic survival. In contrast, C10 did not substantially enhance sensitivity to cisplatin. Genetic loss of REV7 similarly increased sensitivity to colchicine, independently supporting a REV7 dependent vulnerability to microtubule disruption. Combined C10 and colchicine treatment was associated with pronounced alterations in mitotic and post-mitotic nuclear morphology, including condensed/mitotic-like and multinucleated configurations, and increased micronucleus formation. In HT29 cells, combined treatment also increased the frequency of cells containing multiple gamma tubulin positive foci, consistent with disrupted centrosome-associated organization. Together, these findings support a model in which REV7 dependent functions contribute to cellular tolerance and recovery from microtubule mediated mitotic stress, whereas REV7 and REV3 disruption renders CRC cells vulnerable to mitotic perturbation. This study broadens the potential consequences of targeting REV7 beyond its canonical role in TLS and suggests that combining REV7 directed inhibition with mitotic perturbation warrants further investigation as a therapeutic strategy in CRC and potentially other cancers.

cancer biology↗

bioRxiv2026

Impacts of vessel noise on red drum (Sciaenops ocellatus) spawning choruses in Saint Andrew Bay, Florida, U.S.A.

Noise pollution is an increasing threat to soniferous fishes, however, research on noise pollution impacts is limited to few species and rarely studied in situ. Red Drum (Sciaenops ocellatus) is an estuarine, fishery species that choruses during spawning. We tested predictions of the hypothesis that Red Drum alter sound production in response to vessel noise. We used passive acoustic monitoring in 2021 and 2022 at an estuarine inlet and Generalized Least Squares (GLS) models to assess vessel sound exposure levels over time (SEL) and other abiotic parameters on Red Drum chorus SELs. GLS models of daily crepuscular choruses indicated a >5% reduction in proportion to crepuscular vessel noise in 2021. GLS models testing influence of abiotic variables and prior vessel noise, predicted reduced chorus SELs proportional to prior noise SEL: ca. 5% and 3% of vessel SEL in 2021 and 2022, respectively. In some instances, SEL during vessel noise was lower than fish chorus SEL immediately prior, indicating instances when fish reduced chorus amplitude during vessel noise or fled the immediate area. In cases when SEL of vessel noise periods exceeded fish calling SEL immediately prior, it is not known if fish modulated calling amplitude because the portion of combined vessel noise and fish chorus amplitude from vessels is unknown. In peak spawning season (September-October) vessel noise was frequent, detected in >31% of recordings in both years and up to 100% of recordings on some dates. Observations of disrupted choruses and high vessel noise prevalence suggest spawning behavior may be impacted by abundant vessel noise.

animal behavior and cognition↗

bioRxiv2026

Discovery and characterization of small molecule inhibitors of CBL-B that act as intramolecular glue to enhance T-cell anti-tumor activity

CBL-B is a RING-type E3 ubiquitin ligase that acts as a critical negative regulator of T-cell activation. It promotes T-cell anergy and suppresses immune responses through ubiquitin-mediated control of signaling proteins at the immunological synapse. T cells deficient in CBL-B activity lose their dependence on CD28 co-stimulation, exhibit heightened activation and increased cytokine production, and fail to re-establish anergy. In addition, mice deficient in CBL-B activity reject tumors. Together, this cellular mechanism and in vivo phenotype suggest inhibition of CBL-B may be a viable immuno-oncology therapeutic strategy. Here, we report the rational design and execution of a high-throughput screen (HTS) to identify small molecule inhibitors of CBL-B. This campaign led to the discovery of a scaffold that inhibits CBL-B E3 ligase activity with micromolar potency. Structural characterization revealed an intramolecular glue mechanism, in which the compound stabilizes the closed state of CBL-B, preventing phosphorylation of a tyrosine residue that is critical for activation and E2 binding. Iterative structure-activity optimization yielded compounds with nanomolar activity that enhanced T-cell activation and cytokine secretion in primary human T cells and suppressed tumor growth in a syngeneic colorectal mouse model. Together, these studies validate the biological rationale for pharmacological CBL-B inhibition and enabled the de novo discovery of intramolecular CBL-B glue inhibitors. This work culminated in the identification of NX-1607, a first-in-class oral CBL-B inhibitor now in clinical development for cancer immunotherapy.

immunology↗

bioRxiv2026

Synovial lining expressed mechanosensor PIEZO1 drives inflammation-permissive macrophage phenotypes and joint inflammation

Synovial tissue-resident macrophages regulate immune homeostasis within the joint, but can adopt an inflammation-permissive phenotype that promotes immune cell infiltration in rheumatoid arthritis (RA). Understanding the factors that drive this phenotypic switch may help prevent the localisation of inflammation in the joints of individuals at-risk of RA. We identified the mechanosensitive ion channel PIEZO1 as a potential regulator of lining-layer synovial tissue macrophage (STM) function. PIEZO1 was highly expressed in homeostatic, tissue resident TREM2pos lining-layer STMs and in its pathogenic chemokine producing TREM2low phenotype that characterises the hyperplastic lining-layer in active RA. Intra-articular injection of a PIEZO1 agonist in mice induced neutrophil and monocyte infiltration, whereas inhibition of PIEZO1 signalling restored the protective macrophage phenotype. Thus, mechanosensing via PIEZO1 is a defining feature of the joint lining-layer, and its aberrant activation by mechanical stress may lead to the localisation of inflammation within the joint, facilitating a transition from asymptomatic autoimmunity of at-risk RA to clinical disease.

immunology↗