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Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276324 | GEO | 2024/09/05

REPOSITORIES: GEO

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Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer [RNA-seq]

Project description:Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+ macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC , ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+ cells associated with a reactive phenotype and reduced CD8+ T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+ T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.

2023-12-31 | GSE245941 | GEO

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer [ChIP-seq]

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Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

Project description:Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

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Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer [ChIP-seq]

Project description:Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer [ChIP-seq]

| PRJNA1156630 | ENA

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer [RNA-seq]

Project description:Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer [RNA-seq]

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Co-existence of BRAF and NRAS driver mutations in the same melanoma cells results in heterogeneity of targeted therapy resistance.

Project description:Acquired chemotherapeutic resistance of cancer cells can result from a Darwinistic evolution process in which heterogeneity plays an important role. In order to understand the impact of genetic heterogeneity on acquired resistance and second line therapy selection in metastatic melanoma, we sequenced the exomes of 27 lesions which were collected from 3 metastatic melanoma patients treated with targeted or non-targeted inhibitors. Furthermore, we tested the impact of a second NRAS mutation in 7 BRAF inhibitor resistant early passage cell cultures on the selection of second line therapies.We observed a rapid monophyletic evolution of melanoma subpopulations in response to targeted therapy that was not observed in non-targeted therapy. We observed the acquisition of NRAS mutations in the BRAF mutated patient treated with a BRAF inhibitor in 1 of 5 of his post-resistant samples. In an additional cohort of 5 BRAF-inhibitor treated patients we detected 7 NRAS mutations in 18 post-resistant samples. No NRAS mutations were detected in pre-resistant samples. By sequencing 65 single cell clones we prove that NRAS mutations co-occur with BRAF mutations in single cells. The double mutated cells revealed a heterogeneous response to MEK, ERK, PI3K, AKT and multi RTK - inhibitors.We conclude that BRAF and NRAS co-mutations are not mutually exclusive. However, the sole finding of double mutated cells in a resistant tumor is not sufficient to determine follow-up therapy. In order to target the large pool of heterogeneous cells in a patient, we think combinational therapy targeting different pathways will be necessary.

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Population structure across scales facilitates coexistence and spatial heterogeneity of antibiotic-resistant infections.

Project description:Antibiotic-resistant infections are a growing threat to human health, but basic features of the eco-evolutionary dynamics remain unexplained. Most prominently, there is no clear mechanism for the long-term coexistence of both drug-sensitive and resistant strains at intermediate levels, a ubiquitous pattern seen in surveillance data. Here we show that accounting for structured or spatially-heterogeneous host populations and variability in antibiotic consumption can lead to persistent coexistence over a wide range of treatment coverages, drug efficacies, costs of resistance, and mixing patterns. Moreover, this mechanism can explain other puzzling spatiotemporal features of drug-resistance epidemiology that have received less attention, such as large differences in the prevalence of resistance between geographical regions with similar antibiotic consumption or that neighbor one another. We find that the same amount of antibiotic use can lead to very different levels of resistance depending on how treatment is distributed in a transmission network. We also identify parameter regimes in which population structure alone cannot support coexistence, suggesting the need for other mechanisms to explain the epidemiology of antibiotic resistance. Our analysis identifies key features of host population structure that can be used to assess resistance risk and highlights the need to include spatial or demographic heterogeneity in models to guide resistance management.

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Spatial heterogeneity of bone marrow endothelial cells unveils a distinct subtype in the epiphysis.

Project description:Bone marrow endothelial cells (BMECs) play a key role in bone formation and haematopoiesis. Although recent studies uncovered the cellular taxonomy of stromal compartments in the bone marrow (BM), the complexity of BMECs is not fully characterized. In the present study, using single-cell RNA sequencing, we defined a spatial heterogeneity of BMECs and identified a capillary subtype, termed type S (secondary ossification) endothelial cells (ECs), exclusively existing in the epiphysis. Type S ECs possessed unique phenotypic characteristics in terms of structure, plasticity and gene expression profiles. Genetic experiments showed that type S ECs atypically contributed to the acquisition of bone strength by secreting type I collagen, the most abundant bone matrix component. Moreover, these cells formed a distinct reservoir for haematopoietic stem cells. These findings provide the landscape for the cellular architecture in the BM vasculature and underscore the importance of epiphyseal ECs during bone and haematopoietic development.

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TNFα-producing Macrophages Determine Subtype Identity and Prognosis via AP1 Enhancer Reprogramming in Pancreatic Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-02 | GSE173159 | GEO

TNFα-producing Macrophages Determine Subtype Identity and Prognosis via AP1 Enhancer Reprogramming in Pancreatic Cancer

Project description:Global mRNA expression profiling of patient derived pancreatic carcinoma xenograft models (N=4) were collected using Agilent human whole genome array (G4845A AMADID 026652, cRNA 4x44k V2) . Mice were treated daily with JQ1 (50 mg/kg, MedChem express/ Hycultec) to establish response characteristics.

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