Biology subjects

Morris, J. P.

Publications and source records attributed to Morris, J. P..

11 recordsLinked to original sources

bioRxiv2025

p53 and YAP/TAZ-TEAD activities determine metaplastic heterogeneity in pancreatic cancer

BACKGROUND and AIMSPancreatic ductal adenocarcinoma (PDAC) initiation and progression is characterized by lineage plasticity across a continuum of metaplastic and malignant cell fates. This molecular heterogeneity influences disease progression and therapeutic response, yet the genetic and molecular interactions underlying cellular plasticity during PDAC progression remain poorly understood. Here we studied how p53, the most frequently inactivated tumor suppressor in PDAC, interacts with the YAP/TAZ-TEAD transcriptional effector arm of the Hippo pathway to determine cell fate and neoplastic heterogeneity in PDAC development. METHODSWe characterized differentiation states in mouse PDAC and pre-malignant cells in response to p53 activation or inactivation, respectively, and upon genetic, pharmacological, and physiological modulation of YAP/TAZ-TEAD activity. Differentiation was analyzed in vivo in an orthotopic PDAC model permitting independent, inducible control of p53 and TEAD function. We analyzed the effect of p53 and YAP/TAZ-TEAD activity on cell fate in mouse and human PDAC and analyzed markers of clinically relevant molecular subtypes in human PDAC cell lines treated with small molecule TEAD inhibitors. RESULTSRe-engaging wildtype p53 function in KrasMut pancreatic cancer cells increases TEAD activity through accumulation of its co-activator TAZ. Remarkably, increased YAP/TAZ-TEAD activity broadly suppresses the expression of overlapping markers of gastric pit-like (GPL) differentiation and the classical PDAC subtype that are promoted by p53. Accordingly, p53 and YAP/TAZ-TEAD activity inversely correlate with GPL and classical differentiation during PDAC development and modulation of both pathways determines expression of GPL and classical markers in vitro and in vivo. GPL differentiation is acutely sensitive to YAP/TAZ-TEAD activity including oncogenic perturbations of the Hippo pathway, actin dynamics, cell-to-cell contact, and adaptative YAP/TAZ accumulation in response to Ras/MAPK pathway inhibition. Functional repression of gastric-classical differentiation by TEAD persists in human PDAC where potent TEAD inhibition increases expression of GPL and classical markers. CONCLUSIONSWe find that p53 and YAP/TAZ-TEAD activities determine gastric plasticity during PDAC development highlighting the role that key cancer drivers and therapeutically targetable signaling pathways play in active maintenance of cellular identity during pancreatic cancer development.

cancer biology↗

bioRxiv2025

p53 activity licenses transcriptional regulation by YAP/TAZ-TEAD to shape expression landscapes during tumorigenesis

The tumor suppressor p53 is the most frequently disabled gene in cancer, where its inactivation promotes the transition between transcriptionally distinct pre-malignant and malignant disease. How p53 action shapes these stage-dependent expression landscapes is poorly understood. Using a mouse model where p53 function is restored in advanced pancreatic cancer, we demonstrate that p53 dependent gene expression is determined by regulation of YAP/TAZ-TEAD transcriptional complexes at multiple levels of molecular control. Restoration of p53 activity in pancreatic cancer cells expands transcriptional regulation by reorganizing TEAD binding at newly accessible enhancer landscapes, resulting in distinct TEAD-driven gene regulatory networks when p53 is inactivated versus engaged. Furthermore, p53 potentiates expression of newly licensed TEAD targets by increasing TAZ levels in response to the actin remodeling associated with cell cycle arrest and senescence. Thus, p53 activity controls the qualitative and quantitative output of YAP/TAZ-TEAD, including secretory programs involved in tumor-immune communication and remodeling of the microenvironment. Our work nominates regulation of YAP/TAZ-TEAD via p53 as a mechanism that determines stage dependent transcriptional landscapes during stepwise tumorigenesis.

cancer biology↗

bioRxiv2025

Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis

The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we develop for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity and tissue remodeling, revealing a critical window for intercepting malignancy.

cancer biology↗

bioRxiv2025

IFI16 senses and protects stalled replication forks

Replication stress is a key driver of DNA damage and genome instability. Replication stress-induced fork remodelling generates a new DNA end that is vulnerable to the action of nucleases, and which is protected by a range of factors including the canonical tumour suppressors BRCA1 and BRCA2. Here we report that replication stress drives elevated production of cytokines and chemokines in the absence of DNA damage. The DNA sensor IFI16 binds nascent DNA at stalled replication forks and signals via the DNA sensing adaptor STING, to induce the activation of NF-{kappa}B and the production of pro-inflammatory cytokines in response to replication stress. IFI16 also acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11 and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the cross-talk between innate immunity and fork protection during replication stress. HighlightsO_LIReplication stress induces an early innate immune response, which is dependent on the DNA sensing factors IFI16 and STING, but not cGAS C_LIO_LIIFI16 binds directly to nascent DNA at stalled replication forks C_LIO_LIIFI16 prevents nucleolytic degradation of reversed forks C_LIO_LIIFI16 is required for interferon-mediated fork protection in BRCA-deficient cells C_LI

cancer biology↗

bioRxiv2025

Menin-MLL1 complex cooperates with NF-Y to promote HCC survival

Identification of new therapeutic targets in hepatocellular carcinoma (HCC) remains critical. Chromatin regulating complexes are frequently mutated or aberrantly expressed in HCC, suggesting dysregulation of chromatin environments is a key feature driving liver cancer. To investigate whether the altered chromatin state in HCC cells could be targeted, we designed and utilized an epigenome-focused CRISPR library that targets genes involved in chromatin regulation. This focused approach allowed us to test multiple HCC cell lines in both 2D and 3D growth conditions, which revealed striking differences in the essentiality of genes involved in ubiquitination and multiple chromatin regulators vital for HCC cell survival in 2D but whose loss promoted growth in 3D. We found the core subunits of the menin-MLL1 complex among the strongest essential genes for HCC survival in all screens and thoroughly characterized the mechanism through which the menin-MLL1 complex promotes HCC cell growth. Inhibition of the menin-MLL1 interaction led to global changes in occupancy of the complex with concomitant decreases in H3K4me3 and expression of genes involved in PI3K/AKT/mTOR signaling pathway. Menin inhibition affected chromatin accessibility in HCC cells, revealing that increased chromatin accessibility at sites not bound by menin-MLL1 was associated with the recruitment of the pioneer transcription factor complex NF-Y. A CRISPR/Cas9 screen of chromatin regulators in the presence of menin inhibitor SNDX-5613 revealed a significantly increased cell death when combined with NFYB knockout. Together these data show that menin-MLL1 is necessary for HCC cell survival and cooperates with NF-Y to regulate oncogenic gene transcription.

cancer biology↗

bioRxiv2024

Mutant IDH uncouples p53 from target gene regulation to disable tumor suppression

p53 prevents tumor initiation and progression via transcriptional regulation of target gene networks. Here, we find that cancer-associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes the outgrowth of cancer cells with transcriptionally active, wild-type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG)-dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression, resulting in disabled upregulation of targets that execute tumor suppression. Specifically, mutant IDH disrupts the expression of pro-apoptotic p53 targets that enable p53-dependent tumor regressions, including the death ligand receptor Fas. Pharmacological inhibition of mutant IDH in TP53 wild-type cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy-induced apoptosis. Therefore, we implicate the disruption of p53 target gene regulation as a reversible, oncogenic feature of cancer-associated IDH mutations. SIGNIFICANCEWe find that chromatin states altered by cancer-associated IDH mutations intersect with transcriptional regulation of p53 target genes. This reversible interaction may represent a strategy to reinvigorate latent tumor suppression in IDH mutant, p53 wild-type tumors.

cancer biology↗

bioRxiv2023

Epigenetic and neural correlates of selective social attention across adulthood

Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and ones ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene (OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Here we explore age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young and older adults. We find that older adults activate diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We find a significant age-by-OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults display a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association does not hold for older adults. Instead, perceived social support interacts with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior.

neuroscience↗

bioRxiv2023

Functional brain connectivity during social attention predicts individual differences in social skill

Social attention involves selectively attending to and encoding socially relevant information. We investigated the neural systems underlying the wide range of variability in both social attention ability and social experience in a neurotypical sample. Participants performed a selective social attention task while undergoing fMRI and completed self-report measures of social functioning. Using connectome-based predictive modeling, we demonstrated that individual differences in whole-brain functional connectivity patterns during selective attention to faces predicted task performance. Individuals with more cerebellar-occipital connectivity performed better on the social attention task, suggesting more efficient social information processing. Then, we estimated latent communities of autistic and socially anxious traits using exploratory graph analysis to decompose heterogeneity in social functioning between individuals. Connectivity strength within the identified social attention network was associated with social skills, such that more temporal-parietal connectivity predicted fewer challenges with social communication and interaction. These findings demonstrate that individual differences in functional connectivity strength during a selective social attention task are related to varying levels of self-reported social skill.

neuroscience↗

bioRxiv2022

Epigenetic age acceleration predicts subject-specific white matter degeneration in the human brain.

Epigenetic clocks provide powerful tools for estimating health and lifespan but their ability to predict brain degeneration and neuronal damage during the aging process is unknown. In this study, we use GrimAge, an epigenetic clock correlated to several blood plasma proteins, to longitudinally investigate brain cellular microstructure in axonal white matter from a cohort of healthy aging individuals. Given the blood plasma correlations used to develop GrimAge, a specific focus was made on white matter hyperintensities, a visible neurological manifestation of small vessel disease, and the axonal pathways throughout each individuals brain affected by their unique white matter hyperintensity location and volume. 98 subjects over 55 years of age were scanned at baseline with 41 returning for a follow-up scan 2 years later. Using diffusion MRI lesionometry, we reconstructed subject-specific networks of affected axonal tracts and examined the diffusion cellular microstructure composition of these areas, both at baseline and longitudinally, for evidence of cellular degeneration. A chronological age-adjusted version of GrimAge was significantly correlated with baseline WMH volume and markers of neuronal decline, indicated by increased extracellular free water, increased intracellular signal, and decreased axonal signal within WMH. By isolating subject-specific axonal regions lesioned by crossing through a WMH, age-adjusted GrimAge was also able to predict longitudinal development of similar patterns of neuronal decline throughout the brain. This study is the first to establish a relationship between accelerated epigenetic GrimAge and brain cellular microstructure in humans.

neuroscience↗

bioRxiv2022

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.

cancer biology↗

bioRxiv2022

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3/KMT2C) histone methyltransferase occur in a range of solid tumors and heterozygous deletions encompassing MLL3 occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Mll3 cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded genes, Ink4a and Arf. Conversely, elevated MLL3 expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Mll3 restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in MLL3 and CDKN2A display mutual exclusivity in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.

cancer biology↗