Transcriptomic impact of IMA-08401, a novel AHR-agonist resembling laquinimod, on rat liver
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PROVIDER: PRJNA521341 | ENA |
REPOSITORIES: ENA
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Project description:IMA-08401 (C2) represents a novel AHR agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Although both compounds produce an identical AHR-active metabolite, IMA-06201 (DELAQ) in vivo, C2 generates it to a far greater degree. SAHRMs have been proposed as therapeutic options for autoimmune disorders, including multiple sclerosis. So far, clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, more research is required due to the functional resemblance of these compounds to the highly toxic AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here, we report transcriptomic profiling of rat liver following acute (single-dose) and sub-acute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to high doses of C2. Exposure to C2 leads to activation of the AHR, as shown by changes in mRNA abundance of the prototypical AHR-response gene Cyp1a1. We identify a heightened response early after exposure (1 day) that drops off considerably by day 10. Acute exposure to C2 produces a significant immune response, with a focus on antiviral and antibacterial responses that highlights the dual effects of AhR agonists as immunomodulators. Sub-acute exposure leads to an increase in oxidative stress in the liver, the consequences of which require further study on sensitive tissues, such as the CNS and immune system which may be compromised in patients with the target autoimmune disorders.
2019-03-26 | GSE126216 | GEO
Project description: Not available
| S-EPMC6471016 | biostudies-literature
Project description:Expression analysis of colonic neurons stimulated with AhR agonist (3-methylcholanthrene)
| PRJNA589101 | ENA
Project description:Cellular plasticity is a key feature of cancer that enables tumor cells to switch lineage identities, driving disease progression and resistance to therapy. In invasive mucinous adenocarcinoma (IMA), a pronounced pulmonary-to-gastric lineage switch occurs as NKX2.1 is lost and HNF4α, a master regulator of gastric differentiation, is upregulated. Although absent in normal alveolar type 2 cells, HNF4α is aberrantly expressed in most IMA tumors. In this study, we investigate the role of HNF4α within established IMAs and find that it directly activates a gastric differentiation program, particularly in pit cells. Loss of HNF4α disrupts this program and permits FOXA1 and FOXA2 to bind new regulatory sites, leading to the upregulation of neuronal and liver-like gene modules. In light of the poor response of mucinous tumors to KRAS inhibitors, we investigated whether HNF4α modulates sensitivity to KRASG12D targeted therapy. Treatment with MRTX1133 revealed that loss of HNF4α significantly increases IMA sensitivity by reducing the IC50 in vitro and enhancing tumor regression in vivo. Mechanistically, HNF4α deletion impairs cell-cycle progression in drug-tolerant persister cells, while tumors retaining HNF4α maintain these cell-cycle regulators despite KRAS inhibition, promoting persister cell survival. Our findings establish HNF4α as a critical driver of IMA biology governing both gastric differentiation and resistance to KRAS inhibitors and support the development of combination strategies to overcome therapeutic resistance in IMA.
2026-04-23 | GSE294572 | GEO
Project description:Cellular plasticity is a key feature of cancer that enables tumor cells to switch lineage identities, driving disease progression and resistance to therapy. In invasive mucinous adenocarcinoma (IMA), a pronounced pulmonary-to-gastric lineage switch occurs as NKX2.1 is lost and HNF4α, a master regulator of gastric differentiation, is upregulated. Although absent in normal alveolar type 2 cells, HNF4α is aberrantly expressed in most IMA tumors. In this study, we investigate the role of HNF4α within established IMAs and find that it directly activates a gastric differentiation program, particularly in pit cells. Loss of HNF4α disrupts this program and permits FOXA1 and FOXA2 to bind new regulatory sites, leading to the upregulation of neuronal and liver-like gene modules. In light of the poor response of mucinous tumors to KRAS inhibitors, we investigated whether HNF4α modulates sensitivity to KRASG12D targeted therapy. Treatment with MRTX1133 revealed that loss of HNF4α significantly increases IMA sensitivity by reducing the IC50 in vitro and enhancing tumor regression in vivo. Mechanistically, HNF4α deletion impairs cell-cycle progression in drug-tolerant persister cells, while tumors retaining HNF4α maintain these cell-cycle regulators despite KRAS inhibition, promoting persister cell survival. Our findings establish HNF4α as a critical driver of IMA biology governing both gastric differentiation and resistance to KRAS inhibitors and support the development of combination strategies to overcome therapeutic resistance in IMA.
2026-04-23 | GSE320046 | GEO
Project description:Cellular plasticity is a key feature of cancer that enables tumor cells to switch lineage identities, driving disease progression and resistance to therapy. In invasive mucinous adenocarcinoma (IMA), a pronounced pulmonary-to-gastric lineage switch occurs as NKX2.1 is lost and HNF4α, a master regulator of gastric differentiation, is upregulated. Although absent in normal alveolar type 2 cells, HNF4α is aberrantly expressed in most IMA tumors. In this study, we investigate the role of HNF4α within established IMAs and find that it directly activates a gastric differentiation program, particularly in pit cells. Loss of HNF4α disrupts this program and permits FOXA1 and FOXA2 to bind new regulatory sites, leading to the upregulation of neuronal and liver-like gene modules. In light of the poor response of mucinous tumors to KRAS inhibitors, we investigated whether HNF4α modulates sensitivity to KRASG12D targeted therapy. Treatment with MRTX1133 revealed that loss of HNF4α significantly increases IMA sensitivity by reducing the IC50 in vitro and enhancing tumor regression in vivo. Mechanistically, HNF4α deletion impairs cell-cycle progression in drug-tolerant persister cells, while tumors retaining HNF4α maintain these cell-cycle regulators despite KRAS inhibition, promoting persister cell survival. Our findings establish HNF4α as a critical driver of IMA biology governing both gastric differentiation and resistance to KRAS inhibitors and support the development of combination strategies to overcome therapeutic resistance in IMA.
2026-04-23 | GSE294571 | GEO
Project description:Cellular plasticity is a key feature of cancer that enables tumor cells to switch lineage identities, driving disease progression and resistance to therapy. In invasive mucinous adenocarcinoma (IMA), a pronounced pulmonary-to-gastric lineage switch occurs as NKX2.1 is lost and HNF4α, a master regulator of gastric differentiation, is upregulated. Although absent in normal alveolar type 2 cells, HNF4α is aberrantly expressed in most IMA tumors. In this study, we investigate the role of HNF4α within established IMAs and find that it directly activates a gastric differentiation program, particularly in pit cells. Loss of HNF4α disrupts this program and permits FOXA1 and FOXA2 to bind new regulatory sites, leading to the upregulation of neuronal and liver-like gene modules. In light of the poor response of mucinous tumors to KRAS inhibitors, we investigated whether HNF4α modulates sensitivity to KRASG12D targeted therapy. Treatment with MRTX1133 revealed that loss of HNF4α significantly increases IMA sensitivity by reducing the IC50 in vitro and enhancing tumor regression in vivo. Mechanistically, HNF4α deletion impairs cell-cycle progression in drug-tolerant persister cells, while tumors retaining HNF4α maintain these cell-cycle regulators despite KRAS inhibition, promoting persister cell survival. Our findings establish HNF4α as a critical driver of IMA biology governing both gastric differentiation and resistance to KRAS inhibitors and support the development of combination strategies to overcome therapeutic resistance in IMA.
2026-04-23 | GSE294570 | GEO
Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. We found that gut environmental sensor Aryl hydrocarbon receptor (AhR) is induced in colonic neurons in response to microbiota colonisation and regulates intestinal peristalsis in an AhR ligand-dependent manner. In this experiment, we used RNA sequencing to identify genes regulated in mouse colonic neurons by AhR activation.
2019-11-13 | GSE140292 | GEO
Project description:ChIP-seq was done on one lymphoblastoid cell lines for vehicle control, or 3-MC agonist treatment to identify AHR binding regions throughout the genome. We identified 17,688 common binding peaks between all ChIP treatments
2018-07-06 | GSE116632 | GEO
Project description:Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome in a murine model of OVA-induced AAI. To assess differences in Th cell populations CD4+ T cells from the lung tissue were enriched and subjected to sc-RNAseq analysis.
2024-05-06 | E-MTAB-14030 | biostudies-arrayexpress