Biology subjects

Lowe, S. W.

Publications and source records attributed to Lowe, S. W..

At least 19 recordsLinked to original sources

bioRxiv2026

MYC drives endothelial transformation and dedifferentiation in angiosarcoma

MYC amplification is the most common genetic alteration in radiation-associated angiosarcoma and is also present in a subset of de novo primary angiosarcoma, yet its oncogenic role in this vascular malignancy remains unclear. Here, we report that inducible, endothelial-specific MYC overexpression alone was sufficient to drive angiosarcomagenesis in mice. The resulting pulmonary angiosarcoma tumors exhibited impaired endothelial differentiation, indicative of MYC-driven lineage plasticity. Notably, MYC inactivation in dedifferentiated allografts induced growth arrest and restored endothelial gene expression, demonstrating MYC-dependent reversible cellular plasticity. Integrative analyses of MYC ChIP-seq, ATAC-seq, and RNA-seq revealed that overexpressed MYC preferentially occupied highly accessible promoters and activated genes involved in cell growth. Consistent with the murine findings, MYC-amplified human angiosarcomas were enriched for MYC target and cell-cycle programs and depleted of endothelial lineage signatures. MYC overexpression in human endothelial and angiosarcoma cells recapitulated these transcriptional changes, enhanced proliferation, and impaired endothelial tube formation. Together, our results establish MYC as an oncoprotein that promotes endothelial lineage plasticity to drive angiosarcoma initiation and progression.

cancer biology↗

bioRxiv2026

Epigenetic Reactivation of Lineage Differentiation to Target Leukemia

Chromatin regulation critically influences gene expression and cancer progression, yet the functions of chromatin adaptors remain incompletely defined. Using focused CRISPR screening, we identified TRIM28, a multi-domain chromatin adaptor, as a dependency in acute leukemia, where its depletion impaired leukemia cell proliferation in vitro and in vivo, while activating neutrophil differentiation programs. Integrative transcriptomic and chromatin profiling revealed that TRIM28 acts as a co-repressor of neutrophil-associated loci independently of H3K9 methylation, and that TRIM28 loss drives terminal differentiation of leukemia cells into functionally mature neutrophil-like cells with reduced leukemic potential. We developed a selective small-molecule TRIM28 inhibitor that binds the TRIM28 PHD-bromodomain, phenocopies TRIM28 loss across biochemical and cellular assays, exhibits low micromolar anti-leukemia activity, induces neutrophil differentiation, and synergizes with Menin inhibition. Together, these findings, spanning target discovery, mechanism of action, and chemical probe development, establish TRIM28 as a regulator of myeloid cell fate and a promising pro-differentiation therapeutic target in acute leukemia.

cancer biology↗

bioRxiv2026

Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer

Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune-checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

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↗

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↗

bioRxiv2024

Metastatic site influences driver gene function in pancreatic cancer

Driver gene mutations can increase the metastatic potential of the primary tumor1-3, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 - a transcriptional effector of TGF{beta} signaling - which is a hallmark of multiple gastrointestinal malignancies4,5. SMAD4 inactivation mediates TGF{beta}s remarkable anti-to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis6-14. To determine whether metastatic tumors remain dependent on SMAD4 inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enables Smad4 depletion in the pre-malignant pancreas and subsequent Smad4 reactivation in established metastases. As expected, Smad4 inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast, Smad4 reactivation in metastatic disease had strikingly opposite effects depending on the tumors organ of residence: suppression of liver metastases and promotion of lung metastases. Integrative multiomic analysis revealed organ-specific differences in the tumor cells epigenomic state, whereby the liver and lungs harbored chromatin programs respectively dominated by the KLF and RUNX developmental transcription factors, with Klf4 depletion being sufficient to reverse Smad4s tumor-suppressive activity in liver metastases. Our results show how epigenetic states favored by the organ of residence can influence the function of driver genes in metastatic tumors. This organ-specific gene-chromatin interplay invites consideration of anatomical site in the interpretation of tumor genetics, with implications for the therapeutic targeting of metastatic disease.

cancer biology↗

bioRxiv2023

Solid tumor growth depends on an intricate equilibrium of malignant cell states

Control of cell identity and number is central to tissue function, yet principles governing organization of malignant cells in tumor tissues remain poorly understood. Using mathematical modeling and candidate-based analysis, we discover primary and metastatic pancreatic ductal adenocarcinoma (PDAC) organize in a stereotypic pattern whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Leveraging lineage-tracing, we reveal the WNT-R state is transient and gives rise to the WNT-S state that is highly stable and committed to organizing malignant tissue. We further show that a subset of WNT-S cells expressing the Notch ligand DLL1 form a functional niche for WNT-R cells. Genetic inactivation of WNT secretion or Notch pathway components, or cytoablation of the WNT-S state disrupts PDAC tissue organization, suppressing tumor growth and metastasis. This work indicates PDAC growth depends on an intricately controlled equilibrium of functionally distinct cancer cell states, uncovering a fundamental principle governing solid tumor growth and revealing new opportunities for therapeutic intervention.

cancer biology↗

bioRxiv2023

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

cancer biology↗

bioRxiv2023

Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD. SignificanceTreatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy.

cancer biology↗

bioRxiv2023

Cancer cells co-evolve with retrotransposons to mitigate viral mimicry

Overexpression of repetitive elements is an emerging hallmark of human cancers1. Diverse repeats can mimic viruses by replicating within the cancer genome through retrotransposition, or presenting pathogen-associated molecular patterns (PAMPs) to the pattern recognition receptors (PRRs) of the innate immune system2-5. Yet, how specific repeats affect tumor evolution and shape the tumor immune microenvironment (TME) in a pro- or anti-tumorigenic manner remains poorly defined. Here, we integrate whole genome and total transcriptome data from a unique autopsy cohort of multiregional samples collected in pancreatic ductal adenocarcinoma (PDAC) patients, into a comprehensive evolutionary analysis. We find that more recently evolved Short Interspersed Nuclear Elements (SINE), a family of retrotransposable repeats, are more likely to form immunostimulatory double-strand RNAs (dsRNAs). Consequently, younger SINEs are strongly co-regulated with RIG-I like receptor associated type-I interferon genes but anti-correlated with pro-tumorigenic macrophage infiltration. We discover that immunostimulatory SINE expression in tumors is regulated by either Long Interspersed Nuclear Elements 1 (LINE1/L1) mobility or ADAR1 activity in a TP53 mutation dependent manner. Moreover, L1 retrotransposition activity tracks with tumor evolution and is associated with TP53 mutation status. Altogether, our results suggest pancreatic tumors actively evolve to modulate immunogenic SINE stress and induce pro-tumorigenic inflammation. Our integrative, evolutionary analysis therefore illustrates, for the first time, how dark matter genomic repeats enable tumors to co-evolve with the TME by actively regulating viral mimicry to their selective advantage.

cancer biology↗

bioRxiv2022

Rapid generation of precision preclinical cancer models using regulatable in vivo base editing

Single nucleotide variants (SNVs) comprise the majority of cancer-associated genetic changes and can have diverse effects on protein function. Despite a comprehensive catalogue of SNVs across human cancers, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a murine system for temporal and regulatable in vivo cytosine base editing (iBE). The iBE mice show robust, doxycycline-dependent expression across a broad range of tissues with no evidence of DNA or RNA off-target effects. Transient iBE induction drives efficient creation of individual or multiple SNVs in intestinal, lung, and pancreatic organoids, while temporal iBE regulation allows controlled sequential genome editing. Moreover, in situ delivery of plasmid-based or synthetic sgRNAs to target tissues facilitates the simple and rapid generation of pre-clinical cancer models. Overall, iBE is a powerful in vivo platform to define and interrogate the genetic drivers of cancer.

cancer biology↗

bioRxiv2022

Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas

The response to tumor-initiating inflammatory and genetic insults can vary amongst morphologically indistinguishable cells, suggesting yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we perform single-cell analyses on normal, inflamed, pre-malignant and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identify heterogeneous cell-states that are primed for diverse late-emerging neoplastic fates and link these to chromatin remodeling at cell-cell communication loci. Using a new inference approach, we reveal signaling gene modules and tissue-level crosstalk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that we validate by genetic perturbation in mice. Our results uncover a neoplasia-specific tissue remodeling program that may be exploited for pancreas cancer interception. One-Sentence SummarySingle-cell analysis reveals that enhanced epigenetic plasticity drives pro-neoplastic crosstalk in early pancreatic cancer.

cancer biology↗

bioRxiv2022

Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines

Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. This functional heterogeneity is correlated with the existence of transcriptionally distinct subpopulations of CAFs. CAF heterogeneity is observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a remarkably dense and hypoxic stroma that features tumor-restraining myofibroblastic CAFs (myCAFs) and tumor-supporting inflammatory CAFs (iCAFs). While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs display a hypoxic gene expression and biochemical profile and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads fibroblasts to acquire an inflammatory gene expression signature and synergizes with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF-1 dependent fashion. Furthermore, we show that HIF-1 stabilization is sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid co-cultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF-1 as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.

cell biology↗

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

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models that faithfully recapitulate different subtypes of the human disease. To close this gap, we developed methods to somatically introduce different oncogenic lesions directly into the stomach epithelium and show that genotypic configurations observed in patients produce metastatic gastric cancers that recapitulate the histological, molecular, and clinical features of all non-viral molecular subtypes of the human disease. Applying this platform to both wild-type and immune-deficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells that produced distinct patterns of metastasis that were mirrored in patients. Our results establish and credential a highly portable platform for producing autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts aimed at improving outcomes in gastric cancer patients.

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↗

bioRxiv2022

Senescence rewires microenvironment sensing to facilitate anti-tumor immunity

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-{gamma}). Compared to proliferating cells, senescent cells upregulate IFN-{gamma} receptor, become hypersensitized to microenvironmental IFN-{gamma}, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-{gamma} sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance. SIGNIFICANCEOur work identifies a novel interplay between tissue remodeling and tissue sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance anti-tumor immunity.

cancer biology↗

bioRxiv2022

Genome-wide CRISPR guide RNA design and specificity analysis with GuideScan2

We present GuideScan2 for memory-efficient, parallelizable construction of high-specificity CRISPR guide RNA (gRNA) databases and user-friendly gRNA/library design in custom genomes. GuideScan2 analysis identified widespread confounding effects of low-specificity gRNAs in published CRISPR knockout, interference and activation screens and enabled construction of a ready-to-use gRNA library that reduced off-target effects in a novel gene essentiality screen. GuideScan2 also enabled the design and experimental validation of allele-specific gRNAs in a hybrid mouse genome.

genomics↗