Landscape Of Alterations Research Articles

The altered landscape as heterotopia

ABSTRACT This paper considers the contemporary photographic practices of the authors, aligning their conceptual ideas and working methodology with notions of heterotopia. It argues for a positioning within contemporary altered landscape photography that considers place as a heterotopia, a networked system or process that modifies and makes an alternative ‘territory’. In dialogue with a range of relevant authors and artists, the paper contextualises heterotopia and altered landscape spaces as layers of both cultural and ecological intervention. It asserts that an artist in a state of mobility, transit and movement, can effectively employ notions of heterotopia to inform a creative photographic practice. We build on existing heterotopologies through the photographic practices of the authors, altered landscape photography by Australian artist Shane Hulbert, and the cultural investigations of expatriation by Greek artist Ioannis Galanopoulos Papavasileiou. The artists, through phenomenology, lens-based practice and noetic synthesis, approach altered landscape photography from two divergent cultural perspectives; one through the lens of postcolonial national imaging, the other through a trans-national experience of expatriation. We propose that both the cultural and geographic counter-site of an altered landscape, and the social and psychological state of expatriation, are informed by notions of heterotopia, and therefore build on existing heterotopologies.

The Evolving Molecular Landscape and Actionable Alterations in Urologic Cancers

The genetic landscape of urologic cancers has evolved with the identification of actionable mutations that impact diagnosis, prognosis, and therapeutic strategies. This narrative review consolidates existing literature on genetic mutations across key urologic cancers, including bladder, renal, prostate, upper tract urothelial, testicular, and penile. The review highlights mutations in DNA damage repair genes, such as BRCA1/2 and PTEN, as well as pathway alterations like FGFR and PD-L1 overexpression. These mutations influence tumor behavior and therapeutic outcomes, emphasizing the need for precision oncology approaches. Molecular profiling, through tools like next-generation sequencing, has revolutionized patient care by enabling targeted treatment strategies, especially in cancers with distinct molecular subtypes such as luminal or basal bladder cancer and clear cell renal carcinoma. Emerging therapies, including FGFR inhibitors and immune checkpoint blockade, offer new treatment avenues, although resistance mechanisms remain a challenge. We also emphasize the importance of biomarker identification for personalized management, especially in metastatic settings where treatment intensification is often required. Future research is needed to further elucidate our understanding of the genetics affecting urologic cancers, which will help develop novel, individualized therapies to enhance oncologic outcomes.

Enhancing Ecological Education: Utilizing Agent-Based Modeling to Simplify the Impacts of Deforestation on Amphibians

Understanding how deforestation and changes in habitat boundaries affect biodiversity is essential for developing conservation solutions. These topics are central to biology and ecology programs, where students learn to apply their knowledge in real-world conservation efforts. Higher education plays a crucial role in strengthening this understanding, particularly in life sciences programs. Given the complexity of ecological processes in altered landscapes, agent-based modeling provides an interactive and engaging way to simplify and visualize the effects of land use changes. In this study, we integrate Amazonian anurans, highly sensitive to temperature and humidity fluctuations, with an Agent-based model to simulate the impacts of deforestation, habitat restoration, and land abandonment on species survival and movement. Their ectothermic nature and dependence on pulmocutaneous respiration make them especially vulnerable to the drier and more variable conditions caused by deforestation. Integrating this model into conservation biology courses has enhanced learning by encouraging independent exploration, both in and out of the classroom. This tool, an agent-based model, is particularly suited for university-level ecology and conservation courses, and can also serve as an effective awareness tool in environmental education and decision-making workshops, highlighting the negative effects of human-made habitat changes on biodiversity.

The Prominent Role of the Matrix in Ecology, Evolution, and Conservation

As the Anthropocene proceeds, the matrix in which remaining habitats are embedded is an increasingly dominant component of altered landscapes. The matrix appears to have diverse and far-reaching effects, yet our understanding of the causes and consequences of these effects remains limited. We first synthesize the broad range of perspectives on the matrix, provide a generalized framing that captures these perspectives, and propose hypotheses for how and why the matrix matters for ecological and evolutionary processes. We then summarize evidence for these hypotheses from experiments in which the matrix was manipulated. Nearly all experiments revealed matrix effects, including changes in local spillover, individual movement and dispersal, and use of resources in the matrix. Finally, we discuss how the matrix has been, and should be, incorporated into conservation and management and suggest future issues to advance research on and applications of the matrix in ecology, evolution, and conservation.

Epigenomic Reprogramming in Gout

Gout is a crystal-induced arthropathy in which monosodium urate (MSU) crystals precipitate within joints as a result of persistent hyperuricemia and elicit an inflammatory response. An intriguing aspect is the occurrence of gout in only 10–15% of hyperuricemic individuals, suggesting the presence of additional risk factors. Although MSU crystal deposition is widely recognized as the cause of gout flares, the variability in initiating the inflammatory response to hyperuricemia and MSU deposition is not well understood. Several studies bring up-to-date information about the environmental and genetic influences on the progression towards clinical gout. Elevated urate concentrations and exposure to different external factors precipitate gout flares, highlighting the potential involvement of epigenetic mechanisms in gouty inflammation. A better understanding of the alteration of the epigenetic landscape in gout may provide new perspectives on the dysregulated inflammatory response. In this review, we focus on understanding the current view of the role of epigenomic reprogramming in gout and the mechanistic pathways of action.

RUNX1::CBFA2T2 rearranged acute myeloid leukemia transformed from JAK2 V617F mutated primary myelofibrosis

AbstractAcute myeloid leukemia (AML) with RUNX1::CBFA2T2 fusion is rare with largely unknown clinicopathological features and genomic characterization. We present one such case of AML transformed from JAK2 V617F mutated primary myelofibrosis and review the literature on this topic. The immunophenotype and the landscape of cooperative gene alterations in AML with RUNX1::CBFA2T2 resemble those of AML with RUNX1::RUNX1T1, including expression of CD19, cooperative gene alterations in signaling pathway (JAK2), epigenetic/chromatin and cell cycle regulation (TET2, SMC3, and CDKN2A/B), and additional chromosomal abnormalities (trisomies 8 and 15). This case study provides insights into the pathogenesis of this rare subtype of AML.

NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes

BackgroundNF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM.MethodsWe assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1-wildtype and 25 NF1-mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features.ResultsIn our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations (p-adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log2(OR) = − 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1-wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29–8.06, p = 0.01) associated with decreased NF1 expression by IHC.ConclusionNF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.

Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.

To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRAS G12D mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible KRAS variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of KRAS mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRAS G12D second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.

Variation in species-specific responses to habitat fragmentation and land cover structure in urban small mammal communities

Abstract Urbanization is a key driver of habitat loss and fragmentation worldwide, yet many urban ecosystems contain vegetated habitat patches that support diverse wildlife communities. Managing urban systems to support robust wildlife communities requires us to understand the mechanisms that drive the response of species to the urban environment. Small mammals are key components of terrestrial ecosystems (e.g., seed predators, prey) and likely also carry out these roles in urban ecosystems; however, the effects of urbanization on small mammal communities are understudied. To identify how species-specific responses to urban environments shape community composition, we quantified both overall community and species-specific changes in small mammal abundance across an urbanization gradient in a Midwestern US metropolitan area. We combined small mammal trapping and land cover data to generate a hierarchical community abundance model. Species diversity increased with increasing proportional cover of human-modified land cover (i.e., impervious surfaces and turfgrass). This finding is driven by high species diversity on sites bordering streams in mowed parks and low diversity on sites with high tree canopy closure. Additionally, modeling results indicated that species responded differently to landscape attributes, leading to variation in small mammal community composition across the urbanization gradient: prairie-associated species tended to be more abundant in tall vegetation bordering mowed parks while habitat generalists tended to be more abundant on sites with greater canopy closure and shrub cover. Our results suggest that studies that focus on community-level responses (e.g., species richness) to urbanization may miss important species-specific responses. It may be particularly important to assess both species-specific and community-level responses in cities at ecotones (e.g., between forest and grassland) where species with different habitat requirements may replace one another in different types of green spaces, thereby changing community composition without affecting species diversity or richness. Our findings also indicate that vegetated urban patches, especially patches with tall vegetation cover and low canopy cover, are important habitat for prairie-associated small mammal communities, providing conservation options in heavily altered landscapes.

Carbon Sequestration and Landscape Influences in Urban Greenspace Coverage Variability: A High-Resolution Remote Sensing Study in Luohe, China

Urbanization has significantly altered urban landscape patterns, leading to a continuous reduction in the proportion of green spaces. As critical carbon sinks in urban carbon cycles, urban green spaces play an indispensable role in mitigating climate change. This study aims to evaluate the carbon capture and storage potential of urban green spaces in Luohe, China, and identify the landscape factors influencing carbon sequestration. The research combines on-site data collection with high-resolution remote sensing, utilizing the i-Tree Eco model to estimate carbon sequestration rates across areas with varying levels of greenery. The study reveals that the carbon sequestration capacity of urban green spaces in Luohe City is 1.30 t·C·ha−1·yr−1. Among various vegetation indices, the Enhanced Vegetation Index (EVI) explains urban green space carbon sequestration most effectively through an exponential model (R2 = 0.65, AIC = 136.5). At the city-wide scale, areas with higher greening rates, better connectivity, and more complex edge morphology exhibit superior carbon sequestration efficiency. The explanatory power of key landscape indices on carbon sequestration is 78% across the study area, with variations of 71.5%, 62%, and 84.9% for low, medium, and high greening rate areas, respectively. Moreover, when greening rates reach a certain threshold, maintaining and optimizing the quality of existing green spaces becomes more critical than simply expanding the green area. These insights provide valuable guidance for urban planners and policymakers on enhancing the ecological functions of urban green spaces during urban development.

Implications of Coalfield Dynamics on Associated Ecosystems: A Tangential Review

Traditionally, the coal has stood as a resourceful entity for the energy demands of the society. The coalmines are the driving forces in the sufficing the energy and economy of the nation. Certainly, the existence of coal and its excavation is a much aspired endeavours for the development of any society. There are numerous prospective, functional and abandoned coalmines all over the world. Along with the intrinsic worth of the coal excavations, many studies have decisively elucidated the associated environmental complications. The ecological devastation is one of them. The ecological sphere whether it be macro or micro, is a fragile entity and must be taken care of accordingly. The process of coal excavations involves large scale landscape alteration where the entire native vegetation is removed. The ecological domain developed through an extensive period over the landscape vanishes in no time. The hydrological fluctuation also in terms of water chemistry destroys the aquatic habitat prominently known as hydroecology. The microclimatic shift is also a factor affecting drastically on the associated ecologies. The present review article strives to understand the various influencers in the coalfields dominating over the accompanying ecologies through selective endeavours executed all over the world. It also deliberates the probable measures to be taken to shield the associated ecologies in and around coalfields including the sensitization drives for protecting ecologies.

Geographic variability of carbon and nitrogen isotope ratios of nonvolant terrestrial small mammals (Rodentia) across 3 Brazilian biomes

Abstract In this study, we investigated landscape variability of the carbon and nitrogen isotopic composition of nonvolant small mammals in the 3 main Brazilian biomes (Amazon, Atlantic Forest, and Cerrado) while also considering the differential spatial distribution of C4 plants in these biomes. We compiled a subset of data on stable carbon and nitrogen isotope ratios from nonvolant small mammals of the order Rodentia and compared the aggregated isotopic variability at the biome level using classical δ13C–δ15N biplot. The concept of isotopic niche width was used to test whether different foraging attributes drive their isotopic composition, while a Bayesian isotopic mixing model was used to estimate the proportion of 3 main food categories available to these small mammals. We also developed isoscapes in the Brazilian biomes, interpolating animals δ13C and δ15N based on the geographic coordinates of each sample and “sourcescapes” considering geographic variation of the dietary sources. The findings of this study advance our understanding of the foraging ecology of small mammals in biodiversity-rich regions of the Neotropics. Classical methodologies such as stomach content confirmed dietary choices revealed by the stable isotopic composition and also highlighted the importance of C3 and C4 plants in the diet of this group of animals, especially in biomes such as the Atlantic Forest and Cerrado, where there is a predominance of highly altered landscapes. These results confirm that replacing the original vegetation with C4 crops has altered the feeding patterns of small mammals, which could lead to critical ecological changes in the trophic structure of these areas. Vertical stratification of the dietary niche and the interaction between biome and foraging lifestyle were also observed. However, in each biome, there was significant intraspecific and interspecific variation caused by preferences for ingestion of plant and animal material, leading to different degrees of omnivory. Finally, the high local variability between individuals and species requires a larger sampling design that may also contribute to improved spatial resolution of the isoscapes.

Biologically informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post treatment glioblastoma.

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine.

Abstract IA01: Dumpster-diving into the cancer degradome

Abstract Recently, we uncovered a pivotal role for altered proteasome complex composition in shaping tumor immunogenicity in non-small cell lung cancer (NSCLC). Our research demonstrated that the upregulation of a regulatory cap of the proteasome, PSME4, leads to a reduction in antigenic diversity through alterations in proteasomal cleavage patterns, consequently impeding T-cell-mediated anti-tumor immunity. These findings underscore the importance of probing the tumor degradome and its implications for tumor-immune interactions. Yet, numerous questions remain unanswered: Do specific substrates exhibit preferential degradation in PSME4-capped proteasomes? What constitutes their recognition signal? And fundamentally, how do alterations in the degradation landscape influence tumor inflammation? In my talk, I will delve into our latest advancements in addressing these questions, offering insights into the intricate interplay between proteasome-mediated degradation, tumor inflammation, and STAT signaling. Citation Format: Yifat Merbl. Dumpster-diving into the cancer degradome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr IA01.

P1.03C.01 A Landscape of the Driver Alterations in 920 Brazilian Lung Cancer Patients

P1.03C.01 A Landscape of the Driver Alterations in 920 Brazilian Lung Cancer Patients

The Altered Proteomic Landscape in Renal Tubular Epithelial Cells under High Oxalate Stimulation.

Our study aimed to apply a proteomic approach to investigate the molecular mechanisms underlying the effects of oxalate on rat renal tubular epithelial cells. NRK-52E cells were treated with or without oxalate and subjected to quantitative proteomics to identify key proteins and key pathological changes under high oxalate stimulation. A total of 268 differentially expressed proteins (DEPs) between oxalate-treated and control groups were identified, with 132 up-regulated and 136 down-regulated proteins. Functional enrichment analysis revealed that DEPs are associated with oxidative stress, apoptosis, ferroptosis, pro-inflammatory cytokines, vitamin D, and biomineralization. SPP1, MFGE8, ANKS1A, and NAP1L1 were up-regulated in the oxalate-treated cells and the hyperoxaluric stone-forming rats, while SUB1, RNPS1, and DGLUCY were down-regulated in both cases. This altered proteomic landscape sheds light on the pathological processes involved in oxalate-induced renal damage and identifies potential biomarkers and therapeutic targets to mitigate the effects of hyperoxaluria and reduce the risk of CaOx stone formation.

Balancing recreation and flood safety for integrated coastal management: Understanding beach visitors' types of attitude and behaviour in sandy anthropogenic shores

In the Netherlands, with its coastal lowlands, coastal management is performed through sand nourishment and dune utilisation. While policy aims for multifunctionality, coastal management studies predominantly emphasise flood safety, neglecting the recreational function and its interplay with flood safety measures. This study aims to investigate beach visitors' views and behaviour at two reinforced sandy shores in the Netherlands, namely Sand Motor and Hondsbossche Dunes. As the magnitude of the sand-based reinforcements completely changed the original beach landscape, we refer to these as sandy anthropogenic shores (SAS). We conducted surveys to assess SAS visitors' profiles, attitudes (visit motivations, landscape attractiveness), and recreational behaviour (facility preferences, activities, visitation patterns, spatial distribution). We examined differences between SAS and non-SAS beach visitors and compared their perspectives with management expectations. In our analysis, we categorised visitors into three types: local, one-day, and overnight visitors. Our analysis identified three distinct visitor motivation clusters: socialising, relaxation while appreciating beach landscapes, and engaging in sports activities. Natural landscape quality and quietness were the top attractions for SAS visitors. Despite significant human intervention in the design and alteration of the SAS landscape, visitors still appreciate its natural dynamics and beauty. Our analysis indicates that users perceive the SAS as either natural or semi-natural beaches, as intended by their designers and managers. We also developed a conceptual framework of the SAS recreation model based on survey data, forming the foundation for a quantitative model of SAS socio-environmental dynamics in the next phase of our research. Moreover, considering the similarities between SAS and natural shores, we anticipate that our findings will have broad applicability well beyond the specific SAS we have studied.

Single-Hit and Multi-hit PIK3CA Short Variant Genomic Alterations in Clinically Advanced Prostate Cancer: A Genomic Landscape Study.

Tumors harboring two or more PIK3CA short variant (SV) ("multi-hit") mutations have been linked to improved outcomes with anti-PIK3CA-targeted therapies in breast cancer. The landscape and clinical implications of multi-hit PIK3CA alterations in clinically advanced prostate cancer (CAPC) remains elusive. To evaluate the genomic landscape of single-hit and multi-hit PIK3CA genomic alterations in CAPC. The Foundation Medicine FoundationCore database was used to identify 19,978 CAPC tumors that underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA) and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, single-base substitution mutational signatures, and homologous recombination deficiency signature (HRDsig). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). 18,741 (93.8%) tumors were PIK3CA wild type (WT), 1155 (5.8%) featured single PIK3CA SV, and 82 (0.4%) featured multi-hit PIK3CA SVs. Single-hit (6.6 versus 3.8; p < 0.0001) and multi-hit (12.8 versus 3.8; p < 0.0001) featured more driver GA per tumor than PIK3CA WT CAPC, as well as higher prevalence of MMR mutational signature, MSI high status, and TMB levels versus PIK3CA WT (p < 0.0001). Other differences in GA included higher frequencies of GA in BRCA2 in multi-hit versus WT (18.3% versus 8.5%; p = 0.0191), ATM in multi-hit versus WT (13.4% versus 5.6%; p = 0.02) and PTEN in single-hit versus WT (40.2% versus 30.1%; p < 0.0001). Homologous recombination deficiency signatures were higher in PIK3CA WT versus single-hit (11.2% versus 7.6%; p = 0.0002). There were no significant differences in PD-L1 expression among the three groups. Identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique phenotype that may be associated with response to anti-PIK3CA targeted therapy and checkpoint inhibition, supporting relevant clinical trial designs.

Asian elephants involved in conflicts exhibit similar habitat use but travel farther than non-conflict individuals

Rapid development and deforestation in Peninsular Malaysia have degraded and fragmented the tropical forest, impacting the survival of many megafauna species. With reduced space to roam, Asian elephants (Elephas maximus) may extend their range into the altered landscape, leading to human–elephant conflict (HEC). HEC is defined as any interactions between wild elephants and humans that result in negative effects on both humans and elephants. Although known as a keystone species in the region, spatial studies comparing conflict and non-conflict elephants have never been done before. In this study, we used GPS satellite collar data for five conflict and seven non-conflict elephants from 2012 to 2021. We mapped their home ranges, identified hotspots, and estimated the proportion of habitat use (area and time spent) across the Managed Elephant Ranges of Peninsular Malaysia. We found that nine of the 12 elephants spent >90 % of their time in their home range and >95 % of their time in hotspots in forested areas regardless of conflict status. redefining of conflict status as spending <53 % of the time in the home range and <41 % in hotspots in forested areas. However, conflict elephants moved significantly farther on the daily average than non-conflict elephants. Our findings highlight the importance of redefining the conflict status of elephants based on threat levels and habitat use to consider the rapidly degrading habitat that signals human–elephant coexistence.

Exploring epigenetic dynamics unveils a super-enhancer-mediated NDRG1-β-catenin axis in modulating gemcitabine resistance in pancreatic cancer

Chemoresistance remains a formidable challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, necessitating a comprehensive exploration of underlying molecular mechanisms. This work aims to investigate the dynamic epigenetic landscape during the development of gemcitabine resistance in PDAC, with a specific focus on super-enhancers and their regulatory effects. We employed well-established gemcitabine-resistant (Gem-R) PDAC cell lines to perform high-throughput analyses of the epigenome, enhancer connectome, and transcriptome. Our findings revealed notable alterations in the epigenetic landscape and genome architecture during the transition from gemcitabine-sensitive to -resistant PDAC cells. Remarkably, we observed substantial plasticity in the activation status of super-enhancers, with a considerable proportion of these cis-elements becoming deactivated in chemo-resistant cells. Furthermore, we pinpointed the NDRG1 super-enhancer (NDRG1-SE) as a crucial regulator in gemcitabine resistance among the loss-of-function super-enhancers. NDRG1-SE deactivation induced activation of WNT/β-catenin signaling, thereby conferring gemcitabine resistance. This work underscores a NDRG1 super-enhancer deactivation-driven β-catenin pathway activation as a crucial regulator in the acquisition of gemcitabine-resistance. These findings advance our understanding of PDAC biology and provide valuable insights for the development of effective therapeutic approaches against chemoresistance in this malignant disease.