Biology subjects

Kennedy, R.

Publications and source records attributed to Kennedy, R..

10 recordsLinked to original sources

bioRxiv2026

Mutant KRAS dosage contributes to heterogeneity in lung cancer therapeutic response

Oncogenic KRAS mutations promote tumorigenesis by constitutive activation of multiple, well-characterised signalling pathways. However, there is significant heterogeneity across mutant KRAS tumours in terms of mutation present, mutant allele abundance and downstream signalling strength. It is unclear whether these variations can impact responses to specific therapies. Here, we demonstrate that [~]20% of lung adenocarcinomas (LUAD) show an increase in mutant KRAS dosage (KRASmutant allele fraction > KRASwild-type). Furthermore, we show that KRAS mutant dosage can directly influence clinical outcome and therapeutic susceptibilities in lung cancer. Our findings show that mutant KRAS copy gains specifically affect platinum lung cancer response, promoting resistance to this standard-of-care therapy. Importantly, increases in KRAS mutant dosage are also associated with an increased vulnerability to pS6K inhibition, due to the unique metabolic rewiring of these cells. Together, we show that mutant KRAS dosage contributes to the phenotypic heterogeneity of mutant KRAS NSCLC and that assessment of mutant KRAS content or signalling strength can help optimise treatments strategies for these patients.

cancer biology↗

bioRxiv2026

Domesticated pennycress is a self-pollinated crop

CoverCress is a new winter annual oilseed crop developed from field pennycress within the past 20 years. Field pennycress is commonly considered to be self-pollinated but little basic research has been published and there is some misalignment of conclusions. Our experience working with pennycress plant growth in greenhouse and field conditions over the past 13 years suggests that outcrossing is uncommon. We conducted lab, greenhouse, and field experiments to strengthen the body of work. Pollen viability kinetics analysis showed that longevity of pollen viability is negatively impacted by increasing temperatures and by direct exposure to light. Samples treated at 4C declined to 50% viability in 12 hours while it took just 2.5 hrs at 37C, and 1.6 hrs in full sunlight on a cool early April day. Cross-pollination was absent among greenhouse-grown plants flowering inside an agitated plastic pollen-containment covering. Across greenhouse tests, high rates of cross-pollination occurred only in an emasculation treatment that rendered flowers male sterile and opened the pistil to cross-fertilization. Field trials designed to measure pollen flow distance using a trackable fae1 knockout reporter gene failed to show detectable movement of pollen under field conditions in two locations. This data strongly suggests that domesticated field pennycress may be considered a self-pollinated crop and managed as such.

plant biology↗

bioRxiv2026

Injury-induced Cxcl11 and neutrophil signaling drive zebrafish kidney regeneration by generating a nephrogenic niche of Fgf and Wnt expression

Adult zebrafish regenerate their kidneys after injury by activating quiescent renal stem cells, however the injury signals that activate kidney stem cells are not known. We show here that an innate immune, cytokine response after tubule injury is required and sufficient to induce adult zebrafish kidney regeneration. An injury reporter zebrafish transgenic, Tg(kim1:mScarlet3), revealed that tubule injury occurred specifically in kidney proximal tubules and was associated with a rapid accumulation of neutrophils and macrophages. Injury also activated a Tg(NFkB:GFP) reporter transgene specifically in kidney tubules where RNA seq revealed NFkB target gene and cytokine expression. Inhibition of NFkB signaling with JSH-23 blocked Tg(NFkB:GFP) reporter activation and also inhibited induction of new nephrons. Systemic injection of the immune activators lipopolysaccharide or zymosan into uninjured fish rapidly induced cytokine expression followed by nephrogenic gene expression and the appearance of new, functional nephrons. Analysis of injury-induced cytokines revealed that several paralogs of cxcl11 were strongly expressed throughout the regeneration response and injection of recombinant Cxcl11 was sufficient to induce FGF-dependent kidney stem cell aggregation, but not Wnt-dependent epithelial differentiation. Kidney injury in zebrafish expressing a neutrophil dominant negative rac2D57N transgene activated Fgf signaling but failed to induce wnt9b or downstream Wnt target genes. Nephrogenic gene expression and epithelial tubule formation was rescued by treatment with the canonical Wnt agonist CHIR. Our findings demonstrate that an injury-induced, sterile immune response regulates kidney regeneration by establishing a nephrogenic niche of Fgf and Wnt signaling that supports tissue-resident kidney stem cell differentiation into functional nephrons.

developmental biology↗

bioRxiv2026

Plasticity of squamous differentiation drives drug resistance in HNSCC

A critical hallmark of carcinogenesis is the ability of cancer cells to evade the loss of self-renewal normally imposed by terminal differentiation. However, therapies directly attempting to promote differentiation have shown limited efficacy in solid tumours and the cellular mechanisms behind cancer cell persistence are poorly understood. Here we established a patient-derived orthotopic head and neck squamous cell carcinoma (HNSCC) model in vivo that recapitulates the genetic, cellular and histopathological heterogeneity of HNSCC. Experimental induction of differentiation and clonal lineage tracing by fluorescent barcoding revealed a heterogeneous response to terminal differentiation stimuli, enabling subsets of cancer cells to escape differentiation-associated loss of self-renewal. While pharmacological inhibition of ErbB-MEK1/2-ERK1/2 pathway by afatinib could induce the differentiation of patient-derived cancer cells, some highly clonogenic cells remained refractory to differentiation signals even though they were capable of differentiating. Differentiation reporter IVLmCherry further confirmed that differentiation and loss of self-renewal ability were partially uncoupled in patient-derived HNSCC cells. These findings identify differentiation-resistant clonogenic populations as a key barrier to therapeutic efficacy and provide a framework for improving differentiation-based strategies in HNSCC.

cancer biology↗

bioRxiv2025

Thyroid Hormone Receptor Beta Signaling is a Targetable Driver of Prostate Cancer Growth

Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent observations have identified THs as drivers of prostate cancer (PCa) tumor development and progression. We reported that the T3-scavenger protein {micro}-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with the androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor {beta} (TR{beta}), which is the main effector of TH signaling, in the context of PCa. The use of the TR{beta}-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes Nkx3.1 and KLK3 (PSA). NH-3 was a more effective anticancer agent than enzalutamide and showed synergistic properties in combined use. Evidence from human datasets corroborates our findings whereby elevated TR{beta} expression and mutations in TH signaling pathways are associated with the onset of PCa. Collectively, these results establish TR{beta} as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC.

cancer biology↗

bioRxiv2023

Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma

Neuroblastoma (NB), the most common extracranial solid tumor in children, exhibits significant intra-tumoral heterogeneity with two interconvertible identities: adrenergic (ADRN) and mesenchymal (MES). MES cells exhibit phenotypes associated with metastasis and are enriched in relapse NB compared to ADRN. Thus, reprogramming from ADRN to MES may determine inferior NB outcomes, which needs better elucidation. Extracellular matrix (ECM) is an essential tumor microenvironment (TME) component that provides physical support as a scaffold and delivers mechanical cues. We demonstrate that high-risk NB has more topographically aligned ECM fibers than low-risk NB. Using nano-fabricated biomaterials mimicking ECM alignment, we reveal that ECM topography drives ADRN-MES reprogramming by enhancing cell-ECM interactions. This transition involves epigenetic and transcriptional changes, accompanied by enhanced phenotypic features of MES. Also, we uncover that ECM-driven reprogramming relies on the Rho-associated kinase pathway. Overall, ECM-driven ADRN-MES reprogramming provides insight into TME-targeted therapeutic strategies for suppressing MES and improving NB outcomes.

cell biology↗

bioRxiv2023

Cyclic stretch regulates epithelial cell migration in a frequency dependent manner via vinculin recruitment to cell-cell contacts

Epithelial cell migration is critical in regulating wound healing and tissue development. The epithelial microenvironment is incredibly dynamic, subjected to mechanical cues including cyclic stretch. While cyclic cell stretching platforms have revealed responses of the epithelium such as cell reorientation and gap formation, few studies have investigated the long-term effects of cyclic stretch on cell migration. We measured the migratory response of the epithelium to a range of physiologically relevant frequencies and stretch. We integrated our experimental approach with high-throughput cell segmentation to discover a relationship between changes in cell morphology and migration as a function of cyclic stretch. Our results indicate that lower stretch frequencies (i.e., 0.1 Hz) arrest epithelial migration, accompanied by cell reorientation and high cell shape solidity. We found that this response is also accompanied by increased recruitment of vinculin to cell-cell contacts, and this recruitment is necessary to arrest cell movements. This work demonstrates a critical role for frequency dependence in epithelial response to mechanical stretch. These results confirm the mechanosensitive nature of vinculin within the adherens junction, but independently reveal a novel mechanism of low frequency stress response in supporting epithelial integrity by arresting cell migration.

bioengineering↗

bioRxiv2021

Interleukin-6 Drives Key Pathologic Outcomes in Experimental Acetaminophen-induced Liver Failure

Background and AimsIn severe cases of acetaminophen (APAP) overdose, acute liver injury rapidly progresses to acute liver failure (ALF), producing life-threatening complications including, hepatic encephalopathy (HE) and multi-organ failure (MOF). Systemic levels of interleukin-6 (IL-6) and IL-10 are highest in ALF patients with the most severe complications and the poorest prognosis. The mechanistic basis for dysregulation of these cytokines, and their association with outcome in ALF, remain poorly defined. MethodsTo investigate the impact of IL-6 and IL-10 in ALF, we used an experimental setting of failed liver repair after APAP overdose in which a high dose of APAP is administered (i.e., 500-600 mg/kg). Mice were treated with neutralizing antibodies to block IL-6 and IL-10. ResultsIn mice with APAP-induced ALF, high levels of IL-10 reduced monocyte recruitment and trafficking in the liver resulting in impaired clearance of dead cell debris. Kupffer cells in these mice, displayed features of myeloid-derived suppressor cells, including high level expression of IL-10 and PD-L1, which were increased in an IL-6-dependent manner. Similar to ALF patients with HE, cerebral blood flow was reduced in mice with APAP-induced ALF. Remarkably, although IL-6 is hepatoprotective in mice treated with low doses of APAP (i.e., 300 mg/kg), IL-6 neutralization in mice with APAP-induced ALF fully restored cerebral blood flow and reduced mortality. ConclusionCollectively, these studies demonstrate that exaggerated production of IL-6 in APAP-induced ALF triggers immune suppression (i.e., high levels of IL-10 and PD-L1), reduces cerebral blood flow (a feature of hepatic encephalopathy), disrupts liver repair (i.e., failed clearance of dead cells), and increases mortality.

pathology↗

bioRxiv2018

Physical activity in children and adolescents with Charcot-Marie-Tooth disease: A cross-sectional case-controlled study

BackgroundDisability related to the progressive and degenerative neuropathies known as Charcot-Marie-Tooth disease (CMT) affects gait and function, increasing with age and influencing physical activity in adults with CMT. The relationship between disease, ambulatory function and physical activity in children and adolescents with CMT is unknown.\n\nMethodA cross-sectional case-controlled study of 50 children with CMT and age- and gender-matched typically developing (TD) controls [mean age 12.5 (SD 3.9) years]. A 7-day recall questionnaire assessed physical activity; disease severity and gait-related function were measured to explore factors associated with physical activity.\n\nResultsChildren with CMT were less active than TD controls (estimated weekly moderate to vigorous physical activity CMT 283.6 (SD 211.6) mins, TD 318.0 (SD 202.5) mins; p < 0.001). The children with CMT had moderate disability [CMT Pediatric Scale mean score 20 (SD 8) /44] and reduced ambulatory capacity in a six-minute walk test [CMT 485.1 (SD 160.9) metres, TD 639.8 (83.1) metres; p < 0.001]. Physical activity correlated with greater disease severity ({rho} = -0.52, p < 0.001) and six-minute walk distance ({rho} = 0.71, p < 0.001).\n\nConclusionsDisease-related disability affects physical activity and gait-related function in children and adolescents with CMT compared to TD peers. Reduced physical activity adversely affects function across the timespan of childhood and adolescence into adulthood.

neuroscience↗

bioRxiv2018

Forebrain dopamine value signals arise independently from midbrain dopamine cell firing.

The mesolimbic dopamine projection from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is a key pathway for reward-driven learning, and for the motivation to work for more rewards. VTA dopamine cell firing can encode reward prediction errors (RPEs1,2), vital learning signals in computational theories of adaptive behavior. However, NAc dopamine release more closely resembles reward expectation (value), a motivational signal that invigorates approach behaviors3-7. This discrepancy might be due to distinct behavioral contexts: VTA dopamine cells have been recorded under head-fixed conditions, while NAc dopamine release has been measured in actively-moving subjects. Alternatively the mismatch may reflect changes in the tonic firing of dopamine cells8, or a fundamental dissociation between firing and release. Here we directly compare dopamine cell firing and release in the same adaptive decision-making task. We show that dopamine release covaries with reward expectation in two specific forebrain hotspots, NAc core and ventral prelimbic cortex. Yet the firing rates of optogenetically-identified VTA dopamine cells did not correlate with reward expectation, but instead showed transient, error-like responses to unexpected cues. We conclude that critical motivation-related dopamine dynamics do not arise from VTA dopamine cell firing, and may instead reflect local influences over forebrain dopamine varicosities.

neuroscience↗