Biology subjects

Chandra, V.

Publications and source records attributed to Chandra, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Oncogenic KRAS-MAPK signaling sustains a CD73 dependent therapeutic vulnerability in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by oncogenic KRAS signaling and sustained by a desmoplastic, immunosuppressive microenvironment limiting therapeutic response. CD73 mediated adenosine signaling supports this immune-excluded, tumor supportive microenvironment. Whether dual targeting of KRAS-MAPK and CD73 signaling creates a therapeutic opportunity to improve tumor control remains unexplored. Analysis of KRAS mutant cancer cell lines revealed increased expression of NT5E and adenosine receptor ADORA2B. Pharmacologic and genetic suppression of oncogenic KRAS inhibited CD73 expression through a MAPK-dependent program. In syngeneic KPC tumors, conversely, CD73 inhibition with quemliclustat increased ERK phosphorylation in vivo, suggesting adaptive MAPK activation following CD73 blockade. Combined CD73 and RAS(ON) inhibition in vivo produced the strongest antitumor response, reducing endpoint tumor volume beyond either monotherapy. This combination significantly suppressed tumor proliferation and SMA-positive stroma and resulted in a substantial reduction in CD163-positive macrophage infiltration. RAS-MAPK targeted therapy was also associated with increased CD8-positive T cell infiltration and granzyme B-positive staining. As therapeutic responses in PDAC have been linked to the gut microbiome, we further examined treatment-associated changes in the microbiome. RAS-MAPK inhibition produced the most pronounced microbial alterations, which correlated with tumor volume and immune markers. Together, these findings identify KRAS-MAPK driven CD73 signaling as a therapeutic vulnerability in PDAC and support combined CD73 and RAS(ON) inhibition as a strategy to suppress tumor growth, remodel stroma, and alleviate tumor-associated immune suppression.

cancer biology↗

bioRxiv2026

Multi-omics analysis identifies intrinsic Trp53 driven metastatic breast cancer subtypes.

Metastatic breast cancer (mBC) is deadly, and its molecular drivers are largely unknown. Treatment is limited to systemic cytotoxic chemotherapies and tumors often become refractory. The most frequently mutated gene in MBC is TP53. The TP53R248W hotspot missense mutation is associated with poor prognosis. We generated a somatic mouse model of mammary epithelial specific Trp53R245Wexpression. Primary tumors were highly metastatic, reflecting the human molecular subtypes luminal A, luminal B, HER2, and TNBC. Transcriptomic profiling revealed three intrinsic subtypes: stem-cell like (SCL), well-differentiated metabolically active (WDMA), and immunosuppressed (IS). SCL tumors activate ribosome biosynthesis and E2F signaling, amplifying Met, Birc3, Yap1 and deleting Nf1, Pik3r1, and Rad17. WDMA tumors activate cytochrome P450 enzymes, estrogen signaling and branched chain amino acid degradation, with mutations activating Pi3k/Akt/mTOR signaling. IS tumors activate immune suppression, have high mutation burden, and frequently mutate Traf7 and delete Cdkn2a. This is the most comprehensive transcriptomic and genomic profiling of mutant p53-driven breast tumors, elucidating potential therapeutic targets. TeaserA single Trp53 mutation drives intrinsic metastatic breast cancer subtypes with distinct transcriptomes and genomic alterations.

cancer biology↗

bioRxiv2025

Engineered RVG29-Conjugated Chitosan for Enhanced Brain Delivery of Kisspeptin Agonists and Antagonists in Reproductive Health.

Efficient delivery of intact therapeutic peptides across the blood-brain barrier (BBB) remains a central obstacle in translating neuroendocrine modulators to clinical practice. Kisspeptin receptor (KISS1R) agonists and antagonists precisely regulate gonadotropin-releasing hormone (GnRH) pulsatility, thereby controlling luteinizing hormone (LH) release, steroidogenesis, and fertility. While the KISS1R agonist KP10 accelerates GnRH-LH pulses to promote ovulation, the antagonist KP234 suppresses pulse generation, inducing reversible infertility. However, their poor BBB permeability limits clinical application. Here, we engineered a non-invasive brain delivery platform by covalently coupling the rabies virus glycoprotein-derived peptide RVG29 to oxidized chitosan nanoparticles via Schiff base chemistry. Sodium periodate oxidation introduced aldehyde groups, FT-IR confirmed aldehyde formation, and UV-Vis spectroscopy validated RVG29 conjugation through characteristic absorbance shifts. The resulting RVG29 - chitosan carriers demonstrated biocompatibility, enhanced neuronal uptake [~]2.1-fold in vitro, and achieved [~]2.5-fold higher brain accumulation in vivo compared to unconjugated controls. Systemic delivery of RVG29-chitosan-KP10 restored and amplified LH pulsatility in ovariectomized mice, accelerated estrous cycling, increased preovulatory follicle numbers, and enhanced litter size. In contrast, RVG29-chitosan-KP234 abolished LH pulses, maintained animals in persistent diestrus, depleted corpora lutea, and produced complete yet reversible infertility. Longitudinal dosing demonstrated stable neuroendocrine modulation without systemic toxicity, and ovarian histology confirmed ovulatory arrest in antagonist-treated animals. By enabling programmable, bidirectional control of a central hypothalamic circuit through systemic delivery of unmodified peptides, this platform addresses a long-standing barrier in neuroendocrine therapeutics. Beyond fertility regulation, this approach can be adapted to other hypothalamic-driven processes, including metabolic, stress-axis, and circadian control.

bioengineering↗

bioRxiv2025

Distributed neural computation and the evolution of the first brains

The origin of brains in the Precambrian was a landmark in animal evolution, enabling new behavior and life histories. Brains likely evolved from diffuse nerve nets, but we do not know what the first brains looked like or how they were organized. Acoel worms, the likely sister lineage to all other animals with brains, offer a unique window into this transition. Here, we studied the acoel worm Hofstenia miamia, a marine predator that hunts planktonic invertebrates and displays other sophisticated behavior. We found that H. miamia has an unusual diffuse brain: a subepidermal network of dense neuropil exhibiting little regionalization or stereotypy in gross anatomy or distribution of neural cell types. Remarkably, we found that behavior in H. miamia is robust to large, arbitrary amputations of brain regions, suggesting that most regions can perform most computations. More brain tissue improves performance, especially on challenging tasks, but no specific brain region is required. These results lead us to propose that H. miamias brain is composed of computationally pluripotent "tiles" that interact to generate coherent behavior. This architecture suggests a trajectory for nervous system evolution in which early brains may have arisen through the condensation of diffuse nerve nets into unregionalized brains, with regionalization evolving secondarily.

neuroscience↗

bioRxiv2024

Reproductive life history of an acoel worm

Acoel worms belong to an enigmatic and understudied animal lineage in the phylum Xenacoelomorpha. Sparse taxonomic and histological work suggests that these worms exhibit a diversity of reproductive anatomies and likely a corresponding diversity in reproductive behavior. Here, we study the reproductive life history of the three-banded panther worm Hofstenia miamia, an acoel that is emerging as a lab-tractable model system. Using confocal microscopy and histology, we describe H. miamias reproductive organs, identifying structures previously unknown in acoels. Following a cohort of worms from zygote to adulthood, we quantify the developmental dynamics of their reproductive organs, and find that these organs emerge in a stereotyped sequence as a function of increasing body size. Studying the dynamics of organ growth and de-growth during regeneration and in starvation, we show that reproductive organs follow similar growth rules in these contexts, suggesting that they are regulated by a size-associated program in all growth contexts. Finally, we study egg-laying behavior, finding that H. miamia lay their eggs through their mouths after loading them into their pharynges. Worms lay eggs for multiple months after a single mating, suggesting long-term sperm storage despite lacking a storage organ; we also find that worms can lay viable eggs without mating, indicating a capacity for self-fertilization. Further, we show that worms assess their environment to make decisions about when and where to lay their eggs, and sometimes lay eggs in communal clutches. Together, our work establishes foundational knowledge to enable the experimental study of reproductive anatomy, physiology, and behavior in acoels.

zoology↗

bioRxiv2024

Long-term maintenance of patient-specific characteristics in tumoroids from six cancer indications in a common base culture media system

Tumoroids, also known as cancer organoids, are patient-derived cancer cells grown as 3D, self-organized multicellular structures that maintain key characteristics (e.g., genotype, gene expression levels) of the tumor from which they originated. These models have emerged as valuable tools for studying tumor biology, cytotoxicity, and response of patient-derived cells to cancer therapies. However, the establishment and maintenance of tumoroids has historically been challenging, labor intensive, and highly variable from lab to lab, hindering their widespread use. Here, we characterize the establishment and/or expansion of colorectal, lung, head and neck, breast, pancreas, and endometrial tumoroids using the standardized, serum-free Gibco OncoPro Tumoroid Culture Medium. Newly derived tumoroid lines (n=20) were analyzed by targeted genomic profiling and RNA sequencing and were representative of tumor tissue samples. Tumoroid lines were stable for over 250 days in culture and freeze-thaw competent. Previously established tumoroid lines were also transitioned to OncoPro medium and exhibited, on average, similar growth rates and conserved donor-specific characteristics when compared to original media systems. Additionally, OncoPro medium was compatible with both embedded culture in extracellular matrix and growth in a suspension format for facile culture and scale up. An example application of these models for assessing the cytotoxicity of a natural killer cell line and primary natural killer cells over time and at various doses demonstrated the compatibility of these models with assays used in compound and cell therapy development. We anticipate that the standardization and versatility of this approach will have important benefits for basic cancer research, drug discovery, and personalized medicine and help make tumoroid models more accessible to the cancer research community.

cancer biology↗

bioRxiv2023

RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell functionality

Regulatory factor X 6 (RFX6) is indispensable for pancreatic endocrine development and differentiation. The RFX6 protein-truncating variant p.His293LeufsTer7 is significantly enriched in the Finnish population with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 diabetes (T2D) and gestational diabetes. To understand the role of this variant in {beta}-cell development and function, we generated allelic series of isogenic pluripotent stem cell models and directed them into pancreatic islet lineages (SC-islets). Expectedly, in-vitro models of the homozygous RFX6-/- variant failed to generate pancreatic endocrine cells, recapitulating the phenotype in Mitchell-Riley syndrome. Notably, heterozygous RFX6+/- derived SC-islets showed reduced {beta}-cell maturation markers and calcium oscillations, resulting in defective insulin secretion, without affecting {beta}-cell number or insulin content. The reduced insulin secretion is sustained during in-vivo implantation studies, consistent with the susceptibility of the carriers to develop diabetes. TeaserModeling RFX6-assocciated neonatal and type-2 diabetes using allelic series stem cell-derived islets in-vitro and in-vivo.

cell biology↗

bioRxiv2022

Distinct super-enhancer elements differentially control Il2ra gene expression in a cell-type specific fashion

The IL-2 receptor -chain (IL-2R/CD25) is constitutively expressed on DN2/DN3 thymocytes and Treg cells but induced by IL-2 on mature T and NK cells. Il2ra expression is regulated by a super-enhancer extensively bound by STAT5 in mature T cells. Here, we demonstrate that STAT5 cooperates with Notch to induce/maintain Il2ra/CD25 expression in DN2/DN3 cells. Moreover, we systematically investigated CD25 regulation using a series of mice with deletions spanning STAT5 binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, whereas deleting an intronic region primarily decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct elements preferentially control constitutive versus inducible expression in a cell-type-specific manner, with the MED1 coactivator co-localizing with specific STAT5 binding sites. Moreover, the intronic region was a dominant element whose deletion altered the structure throughout the super-enhancer in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating ways to manipulate CD25 expression in a cell-type specific fashion.

immunology↗

bioRxiv2022

The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic {beta}-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-I interferon (IFN) mediated intracellular signaling. To study the role of TYK2 in human pancreatic {beta}-cell development and response to IFN, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromised the emergence of endocrine precursors by regulating KRAS expression while mature stem cell-islets (SC-islets) function was not affected. In the maturing SC-islets, the loss or inhibition of TYK2 prevented IFN-induced antigen processing and presentation, including MHC Class I expression in pancreatic endocrine and progenitor cells. Furthermore, in a CD8+ cytotoxic T-cell co-culture model, the survival of {beta}-cells was enhanced by a selective TYK2 inhibitor. These results identify an unsuspected role for TYK2 on {beta}-cell development and support TYK2 inhibition in adult {beta}-cells as a potent therapeutic target to halt T1D progression.

molecular biology↗

bioRxiv2021

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/470415v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@14625org.highwire.dtl.DTLVardef@1a43372org.highwire.dtl.DTLVardef@12dc0c8org.highwire.dtl.DTLVardef@cbb835_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Adar1 deletion causes degeneration of exocrine pancreas via Mavs-dependent interferon signaling

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine(A) to inosine(I). A-to-I editing alters post-transcriptional RNA processing making ADAR1 a critical regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we specifically deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth likely due to malabsorption associated with exocrine pancreas insufficiency. Analyses of pancreases revealed ductal expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. In addition, we observed an increased prevalence of CD4+ T and natural killer cells in their splenic tissue. These results indicate an association between loss of pancreatic Adar1 with dysregulation of systemic immunity. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis. Summary statementThis work defines the role of Adar1 in pancreatic development and homeostasis.

developmental biology↗

bioRxiv2021

An internal expectation guides Drosophila egg-laying decisions

When presented with two egg-laying substrates, Drosophila lay most of their eggs on the option with higher relative value. How do flies make this relative-value decision? Might the strategy they use allow them to choose the best option even when they experience substrates with a more complex spatiotemporal profile than in canonical two-choice paradigms? We measured Drosophila egg-laying behavior in diverse substrate environments. In all cases, we found that flies dynamically increase or decrease their egg-laying rates as they explore substrates for a deposition site so as to target eggs to the best, recently visited option. Visiting the best option typically led to a strong reduction in egg laying on other substrates for several minutes, with this timescale varying across fly strains. Our data support a model in which flies compare the value of the current substrate with an internally constructed expectation on the value of available options to regulate the likelihood of laying an egg. We show that dopamine-neuron activity is critical for learning and/or expressing this expectation, similar to its role in certain tasks in vertebrates. Integrating sensory experiences over minutes to generate an internal sense of the quality of available options, i.e., forming an expectation, allows flies to use a dynamic reference point for judging the current substrate and might be a general way in which decisions are made, even beyond flies and egg laying.

neuroscience↗

bioRxiv2021

Functional, metabolic and transcriptional maturation of stem cell derived beta cells

Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in stem cell-derived islet (SC-islet) generation, detailed characterization of their functional properties has not been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and comprehensively benchmarked them against primary adult islets. Biphasic glucose stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and increased alpha cells. Electrophysiology and exocytosis of SC-islets were comparable to adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of murine engraftment revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.

developmental biology↗

bioRxiv2020

COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types.

Common genetic polymorphisms associated with severity of COVID-19 illness can be utilized for discovering molecular pathways and cell types driving disease pathogenesis. Here, we assessed the effects of 679 COVID-19-risk variants on gene expression in a wide-range of immune cell types. Severe COVID-19-risk variants were significantly associated with the expression of 11 protein-coding genes, and overlapped with either target gene promoter or cis-regulatory regions that interact with target promoters in the cell types where their effects are most prominent. For example, we identified that the association between variants in the 3p21.31 risk locus and the expression of CCR2 in classical monocytes is likely mediated through an active cis-regulatory region that interacted with CCR2 promoter specifically in monocytes. The expression of several other genes showed prominent genotype-dependent effects in non-classical monocytes, NK cells, B cells, or specific T cell subtypes, highlighting the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.

immunology↗

bioRxiv2020

Colony expansions underlie the evolution of army ant mass raiding

Collective behavior emerges from local interactions between group members, and natural selection can fine-tune these interactions to achieve different collective outcomes. However, at least in principle, collective behavior can also evolve via changes in group-level parameters. Here, we show that army ant mass raiding, an iconic collective behavior in which many thousands of ants spontaneously leave the nest to go hunting, has evolved from group raiding, in which a scout directs a much smaller group of ants to a specific target. We describe the structure of group raids in the clonal raider ant, a close relative of army ants. We find that the coarse structure of group raids and mass raids is highly conserved, and that army ants and their relatives likely follow similar behavioral rules, despite the fact that their raids differ strikingly in overall appearance. By experimentally increasing colony size in the clonal raider ant, we show that mass raiding gradually emerges from group raiding without altering individual behavioral rules. This suggests a simple mechanism for the evolution of army ant mass raids, and more generally that scaling effects may provide an alternative mechanism for evolutionary transitions in complex collective behavior.

evolutionary biology↗

bioRxiv2020

Filamentous Bacteriophage Delay Healing of Pseudomonas-Infected Wounds

We have identified a novel role for filamentous bacteriophage in the delayed healing associated with chronic Pseudomonas aeruginosa (Pa) wound infections. Pf phage delays wound re-epithelialization in the absence of live Pa, indicative that Pf effects on wound healing are independent of Pa pathogenesis. Pf phage directly inhibits autocrine signaling of CXCL1 (KC) to impede keratinocyte migration and wound re-epithelization. In agreement with these studies, a prospective cohort study of 36 human patients with chronic Pa wound infections revealed that wounds infected with Pf positive strains of Pa took longer to heal and were more likely to increase in size compared to wounds infected with Pf negative strains. Together, these data implicate Pf phage in the delayed wound healing associated with Pa infection through direct manipulation of mammalian target cells. We propose that Pf phage may have potential as a biomarker and therapeutic target in delayed wound healing.

microbiology↗

bioRxiv2020

Emergent behavioral organization in heterogeneous groups of a social insect

The composition of social groups has profound effects on their function, from collective decision-making to foraging efficiency. But few social systems afford sufficient control over group composition to precisely quantify its effects on individual and collective behavior. Here we combine experimental and theoretical approaches to study the effect of group composition on individual behavior and division of labor (DOL) in a social insect. Experimentally, we use automated behavioral tracking to monitor 120 colonies of the clonal raider ant, Ooceraea biroi, with controlled variation in three key correlates of social insect behavior: genotype, age, and morphology. We find that each of these sources of heterogeneity generates a distinct pattern of behavioral organization, including the amplification or dampening of inherent behavioral differences in colonies with mixed types. Theoretically, we use a well-studied model of DOL to explore potential mechanisms underlying the experimental findings. We find that the simplest implementation of this model, which assumes that heterogeneous individuals differ only in response thresholds, could only partially recapitulate the empirically observed patterns of behavior. However, the full spectrum of observed phenomena was recapitulated by extending the model to incorporate two factors that are biologically meaningful but theoretically rarely considered: variation among workers in task performance efficiency and among larvae in task demand. Our results thus show that different sources of heterogeneity within social groups can generate different, sometimes non-intuitive, behavioral effects, but that relatively simple models can capture these dynamics and thereby begin to elucidate the basic organizational principles of DOL in social insects. Significance StatementWhen individuals interact in an aggregate, many factors that are not known a priori affect group dynamics. A social group will therefore show emergent properties that cannot easily be predicted from how its members behave in isolation. This problem is exacerbated in mixed groups, where different individuals have different behavioral tendencies. Here we describe different facets of collective behavioral organization in mixed groups of the clonal raider ant, and show that a simple theoretical model can capture even non-intuitive aspects of the behavioral data. These results begin to reveal the principles underlying emergent behavioral organization in social insects. Importantly, our insights might apply to complex biological systems more generally and be used to help engineer collective behavior in artificial systems.

animal behavior and cognition↗

bioRxiv2020

DNA Methylation Repels Binding of HIF Transcription Factors to Maintain Tumour Immunotolerance

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSHypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia. ResultsHere, we report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modelling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid-down by the differential expression and binding of other transcription factors under normoxia control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated. Genetic and pharmacological DNA demethylation, but also cancer-associated DNA hypomethylation, expose these binding sites, inducing HIF-dependent expression of cryptic transcripts. In line with such cryptic transcripts being more prone to cause double-stranded RNA and viral mimicry, we observe low DNA methylation and high cryptic transcript expression in tumours with high immune checkpoint expression, but not in tumours with low immune checkpoint expression, where they would compromise tumour immunotolerance. In a low-immunogenic tumour model, DNA demethylation upregulates cryptic transcript expression in a HIF-dependent manner, causing immune activation and reducing tumour growth. ConclusionsOur data elucidate the mechanism underlying cell-type specific responses to hypoxia, and suggest DNA methylation and hypoxia to underlie tumour immunotolerance.

genomics↗