Biology subjects

Keith, D.

Publications and source records attributed to Keith, D..

10 recordsLinked to original sources

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2025

Tumor-intrinsic MHC-II activation in pancreatic ductal adenocarcinoma enhances immune response and treatment efficacy

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) and poor prognosis. While major histocompatibility complex class II (MHC-II) expression is traditionally associated with professional antigen-presenting cells, its role in PDAC malignant cells remains underexplored. Herein, we utilized single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA sequencing, multiplex immunohistochemistry (mIHC) and ex vivo studies in culture with both human and murine models to investigate the prognostic relevance of MHC-II expression in malignant PDAC cells. Elevated MHC-II expression in malignant cells was strongly associated with increased infiltration of CD4+ T and CD8+ T cells in human PDAC, and pronounced co-localization with plasma cells, indicative of an antigen-activated immune microenvironment. In the KPC mouse model of PDAC, pharmacologic induction of MHC-II expression by cobimetinib treatment in malignant epithelial cells significantly enhanced the therapeutic response to immune checkpoint blockade (ICB). These findings highlight the role of malignant cell- intrinsic MHC-II expression in promoting antigen presentation and fostering an anti-tumor immune microenvironment. Our results position MHC-II as a promising prognostic biomarker and therapeutic target in PDAC, paving the way for novel immunomodulatory strategies. Summary of highlightsSingle-cell and spatial transcriptomic analyses reveal that elevated MHC-II expression in malignant PDAC cells correlates with increased infiltration of CD4 and CD8 T cells. Stimulating MHC-II expression in tumors effectively enhances immunotherapeutic responses to ICB in the PDAC KPC mouse model, including PDAC tumors previously resistant to therapeutic interventions. MHC-II serves as a prognostic biomarker and a promising target for immunotherapy in PDAC.

cancer biology↗

bioRxiv2025

Long Noncoding RNAs Enforce Pancreatic Cancer Identity and Block Reprogramming

The Yamanaka factors (OCT4, SOX2, KLF4, and MYC; OSKM) can rejuvenate aging phenotypes in somatic cell types by resetting the epigenetic landscape. Curiously, most solid tumor cells remain largely resistant to reprogramming despite their well-documented plasticity, and the underlying mechanisms are unclear. Here, we combined genomic profiling and in vivo assays to investigate OSKM-mediated reprogramming of pancreatic ductal adenocarcinoma (PDAC). In the initial stages, we found that cancer-specific genes were refractory while mesodermal/ECM programs, normally silenced by PRC2, were aberrantly upregulated. A CRISPR interference screen for OSKM reprogramming coupled with functional analyses revealed that suppression of cancer-associated long noncoding RNAs (lncRNAs) erased malignant epithelial programs, restored tumor suppressor activity, and impaired tumorigenicity in vivo. We further identified that ATXN7L3-AS1 lncRNA sustains the PDAC malignant identity through its association with active epithelial oncogenic programs and poised PRC2-targeted developmental genes, thereby supporting both plasticity and memory. Thus, by exploring why cancer cells are resistant to reprogramming, we identify lncRNAs as gatekeepers of malignant identity, suggesting that targeting lncRNAs could be a generalizable therapeutic strategy in treating solid tumors.

cancer biology↗

bioRxiv2025

Quantifying the hydrological niche of swamp vegetation communities using indicator species

Indicator species are typically used to infer the presence of other biota or specific environmental conditions. Here we use indicator species to quantify the hydrological niche of their corresponding vegetation communities within Coastal Upland Swamps of the Sydney Basin Bioregion, Australia. Swamp vegetation organizes naturally into five recognised communities, thought to occupy distinct positions along a hydrological gradient. However, longwall mining reduces hydro-period, potentially impacting the observed vegetation. We modelled the hydrological niche for each community using the relative frequency of 20 vascular plant indicator species (four for each community) and time series soil moisture data from 11 unmined sites across four swamps. We then used this model to predict indicator species frequencies in 3 mine-impacted sites. Indicator species were modelled as a function of the average number of days-per-year that swamps remained saturated at the base of the root zone (30 cm below surface). Hydrological niches were well differentiated for four communities with the estimated optimal mean annual days-per-year saturated ranging from Restioid heath at 16 [<16, 29] (mean {+/-} [95% uncertainty]) to Ti-tree thicket at 352 [322, >353]. Banksia thicket 96 [65, 154] and Cyperoid heath 257 [204, 297] communities were intermediate. However, Sedgeland indicator species showed limited variation with changing saturation, and their hydrological niche remains unclear. The model under-predicted the frequency of Cyperoid heath and over-predicted Banksia thicket indicator species in mine-impacted sites, suggesting vegetation is not yet in equilibrium with hydrology. Results suggest indicator species can provide a reliable basis for determining the hydrological niche of wetland plant communities, which can in turn predict community-level impacts of hydrological change.

ecology↗

bioRxiv2025

PIN1 Drives Cellular Plasticity and Immune Modulation in Chronic Pancreatitis

Background and AimsChronic pancreatitis (CP) is characterized by inflammation, fibrosis, and acinar-to-ductal metaplasia (ADM). PIN1, known to drive oncogenic signaling and cellular plasticity in cancer, has an unexplored role in CP. This study investigates PIN1s expression and function in CP pathogenesis using human tissues and mouse models. MethodsPIN1 expression was assessed in human CP tissue microarrays (TMAs) via immunohistochemistry (IHC) and cyclic immunofluorescence (CyCIF). Acute and chronic pancreatitis were induced in wild-type (WT) and PIN1 knockout (PIN1KO) mice using caerulein. Disease progression was monitored histologically, and immune profiling was conducted using flow cytometry. Pharmacological inhibition was performed using a small molecule PIN1 inhibitor-Sulfopin, and effects were evaluated by histology, qPCR, and cytokine analysis. Single-cell RNA sequencing (scRNA-seq) was performed on pancreatic tissues to perform pathway analysis and intercellular communication. ResultsPIN1 expression was elevated in human CP tissues, correlating with disease severity and ADM. In mice, both acute and chronic pancreatitis increased PIN1 expression, but only in our chronic PIN1KO mice displayed reduced pancreatic injury, fibrosis, ADM, and modulated immune infiltration. Pharmacological PIN1 inhibition mimicked the protective effects of genetic knockout, dampening inflammatory pathways. scRNA-seq revealed that PIN1 inhibition altered the intercellular communication networks between epithelial, immune, and stromal cells. ConclusionPIN1 drives cellular plasticity, immune modulation, and disease progression in CP. Targeting PIN1 may offer a therapeutic strategy to mitigate CP. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/653850v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@67f9fcorg.highwire.dtl.DTLVardef@4d4c1forg.highwire.dtl.DTLVardef@c099d7org.highwire.dtl.DTLVardef@b41aa5_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Shah, V. (2025) https://BioRender.com/undefined

cell biology↗

bioRxiv2025

HMG box-containing protein 1 (HBP1) prevents pancreatic injury in experimental pancreatitis but accelerates pancreatic neoplasia progression

Background & AimsPancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG- box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown. MethodsWe examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared to their littermate controls. Spatial transcriptomics and multiplexed protein assays, histological analysis, and immunostaining were utilized to characterize pathological changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells. ResultsHBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions. ConclusionsHBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.

cell biology↗

bioRxiv2022

Effects of hydrological change in fire-prone wetland vegetation: an empirical simulation

Upland swamps are peat-accumulating, groundwater-dependent and fire-prone wetland ecosystems. Drying caused by anthropogenic processes such as underground mining, ditching and climate change may disrupt surface and groundwater flows effecting a bottom-up control on wetland expression. Fire is an endogenous, recurring disturbance that drives a top-down consumptive force in many of these systems. When compounded with anthropogenic drying, fire may facilitate permanent community transitions. A dearth of ecological data and temporal lags have hampered our ability to predict risks associated with multiple disturbances in wetland plant communities. We collected intact wetland mesocosms from valley floors and lower slopes of four undisturbed swamp sites. We transferred the mesocosms to a glasshouse and established three different soil moisture availability levels to simulate wetland drainage. After 20 months of the hydrological treatment, we simulated a fire event by sequentially applying biomass removal (clipping), heat and smoke to half of the mesocosms. We monitored species biomass, richness and composition over a 3.5-year time frame. We found evidence of a temporal lag in biomass response to low water availability and synergistic hydrological and fire effects on species richness. In unburnt conditions, richness declined with low water availability but was maintained under high and medium water availability. After simulated fire in medium water availability, however, richness also declined and converged with depauperate low water mesocosm richness. Representation by many obligate swamp species declined in low compared with high water availability mesocosms over time, an effect that was amplified by the fire treatment. SynthesisOur evidence of lagged effects of hydrological change on wetland vegetation and compounding effects of fire should be considered in impact assessments, monitoring programs and ecosystem management to avoid irreversible wetland change in drying environments.

ecology↗

bioRxiv2022

Ongoing Replication Stress Response and New Clonal T Cell Development Discriminate Between Liver and Lung Recurrence Sites and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

Background and AimsMetastatic pancreatic adenocarcinoma (mPDAC) is lethal, yet a subset of patients who have metastatic disease that spreads only to the lung have better outcomes. We identified unique transcriptomic and immune features that distinguish patients who develop metastases in the liver (liver cohort) versus those with lung-avid but liver-averse mPDAC (lung cohort). MethodsWe used clinical data from the Oregon Pancreas Tissue Registry to identify PDAC patients with liver and/or lung metastases. Gene expression and genomic alteration data from 290 PDAC tumors were used to identify features unique to patients from the liver and lung cohorts. In parallel, T cell receptor sequencing data from 289 patients were used to identify immune features unique to patients in the lung cohort. ResultsLung cohort patients had better survival outcomes than liver cohort patients. Primary tumors from patients in the liver cohort expressed a novel gene signature associated with ongoing replication stress (RS) response predictive of poor patient outcome independent from known subtypes. In contrast, patients with tumors lacking the RS response signature survived longer, especially if their tumors had alterations in DNA damage repair genes. A subset of patients in the lung cohort demonstrated new T cell clonal development in their primary and metastatic tumors leading to diverse peripheral blood TCR repertoires. ConclusionLiver-avid metastatic PDAC is associated with an ongoing RS response, whereas tumors lacking the RS response with ongoing T cell clonal responses may have unique vulnerabilities allowing long-term survival in patients with lung-avid, liver-averse metastatic PDAC.

cancer biology↗

bioRxiv2020

Global shortfalls in extinction risk assessments for endemic flora

The Global Strategy for Plant Conservation (GSPC) ambitiously calls for an assessment of extinction risk for all recognised plant taxa by 20201. It is now clear that this target will not be met in the short-term; only 21-26% of known plant species have been assessed2 - a monumental shortfall in anticipated knowledge. Yet the need for risk assessments has never been more urgent. Plants are rapidly going extinct3,4 and face threats such as climate change5 and permanent deforestation6. Extinction risk assessments continue to provide the critical foundation to inform protection, management and recovery of plant species7,8, the loss of which will have clear consequences for maintaining planetary systems and human well-being9. Here, we rank countries of the world based on progress towards assessing the extinction risk to their endemic flora. Overall, 67% of country-based endemic species do not have an extinction risk assessment completed (143,294 species). We show that some of the worlds wealthiest nations, which also have relatively strong species protections, are failing to protect their unique flora by not systematically assessing risks to their endemic species.

ecology↗

bioRxiv2016

The Monarch Initiative: Insights across species reveal human disease mechanisms

The principles of genetics apply across the whole tree of life: on a cellular level, we share mechanisms with species from which we diverged millions or even billions of years ago. We can exploit this common ancestry at the level of sequences, but also in terms of observable outcomes (phenotypes), to learn more about health and disease for humans and all other species. Applying the range of available knowledge to solve challenging disease problems requires unified data relating genomics, phenotypes, and disease; it also requires computational tools that leverage these multimodal data to inform interpretations by geneticists and to suggest experiments. However, the distribution and heterogeneity of databases is a major impediment: databases tend to focus either on a single data type across species, or on single species across data types. Although each database provides rich, high-quality information, no single one provides unified data that is comprehensive across species, biological scales, and data types. Without a big-picture view of the data, many questions in genetics are difficult or impossible to answer. The Monarch Initiative (https://monarchinitiative.org) is an international consortium dedicated to providing computational tools that leverage a computational representation of phenotypic data for genotype-phenotype analysis, genomic diagnostics, and precision medicine on the basis of a large-scale platform of multimodal data that is deeply integrated across species and covering broad areas of disease.

evolutionary biology↗