Characterization of tumor-associated endothelial cells and the development of a prognostic model in pancreatic ductal adenocarcinoma

Wu, Jun; Liu, Yang; Fu, Qi; Cao, Zhi; Ma, Xiaodong; Li, Xun

doi:10.1016/j.bbagen.2023.130545

Cited by 3 publications

(1 citation statement)

References 51 publications

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“…Recently, a scRNA-seq analysis identified a Hoxd9 + Col4A1 + ECs cluster with progenitor characteristics predominant in the actively expanding neovasculature of tumors compared to normal samples [46]. It would be interesting to analyze whether hypoxia has a differential effect on the proliferation of Hoxd9 + versus Hoxd9 - ECs in the vascular structures of the EBs.…”

Section: Discussionmentioning

confidence: 99%

Bhlhe40 limits proliferation and prevents excessive angiogenesis in mouse embryoid bodies under hypoxia

Acosta-Iborra,

Gil-Acero,

Sanz-Gómez

et al. 2024

Preprint

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Knowledge of the molecular mechanisms that underlie the regulation of the major adaptive responses to an unbalanced oxygen tension is central to understanding tissue homeostasis and disease. Hypoxia-inducible transcription factors (HIFs) coordinate changes in the transcriptome that control these adaptive responses. Here, we focused on the functional role of the transcriptional repressor basic-helix-loop-helix family member e40 (Bhlhe40), which we previously identified in a meta-analysis as one of the most consistently up-regulated genes in response to hypoxia across various cell types. We investigated the role of Bhlhe40 in controlling proliferation and angiogenesis using a gene editing strategy in mouse embryonic stem cells (mESCs) that we differentiated in embryoid bodies (EBs). We observed that hypoxia-induced Bhlhe40 expression was compatible with the rapid proliferation of pluripotent mESCs under low oxygen tension. However, in EBs, hypoxia triggered a Bhlhe40-dependent cell cycle arrest in most progenitor cells and endothelial cells within vascular structures. Furthermore, Bhlhe40 knockout increased the basal vascularization of the EBs in normoxia and exacerbated the hypoxia-induced vascularization, supporting a novel role for Bhlhe40 as a negative regulator of blood vessel formation. Our findings implicate Bhlhe40 in mediating key functional adaptive responses to hypoxia, such as proliferation arrest and angiogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Bhlhe40 limits proliferation and prevents excessive angiogenesis in mouse embryoid bodies under hypoxia

Acosta-Iborra,

Gil-Acero,

Sanz-Gómez

et al. 2024

Preprint

View full text Add to dashboard Cite

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Tumor Microenvironment Landscapes Supporting EGFR-mutant NSCLC Are Modulated at the Single-cell Interaction Level by Unesbulin Treatment

Maroni,

Krishnan,

Alfieri

et al. 2024

Cancer Research Communications

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Lung cancer is the leading cause of cancer deaths. Lethal pulmonary adenocarcinomas (ADC) present with frequent mutations in the EGFR. Genetically engineered murine models of lung cancer expedited comprehension of the molecular mechanisms driving tumorigenesis and drug response. Here, we systematically analyzed the evolution of tumor heterogeneity in the context of dynamic interactions occurring with the intermingled tumor microenvironment (TME) by high-resolution transcriptomics. Our effort identified vulnerable tumor-specific epithelial cells, as well as their cross-talk with niche components (endothelial cells, fibroblasts, and tumor-infiltrating immune cells), whose symbiotic interface shapes tumor aggressiveness and is almost completely abolished by treatment with Unesbulin, a tubulin binding agent that reduces B cell–specific Moloney murine leukemia virus integration site 1 (BMI-1) activity. Simultaneous magnetic resonance imaging (MRI) analysis demonstrated decreased tumor growth, setting the stage for future investigations into the potential of novel therapeutic strategies for EGFR-mutant ADCs. Significance: Targeting the TME is an attractive strategy for treatment of solid tumors. Here we revealed how EGFR-mutant landscapes are affected at the single-cell resolution level during Unesbulin treatment. This novel drug, by targeting cancer cells and their interactions with crucial TME components, could be envisioned for future therapeutic advancements.

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Bhlhe40 Regulates Proliferation and Angiogenesis in Mouse Embryoid Bodies under Hypoxia

Acosta-Iborra,

Gil-Acero,

Sanz-Gómez

et al. 2024

IJMS

View full text Add to dashboard Cite

Knowledge of the molecular mechanisms that underlie the regulation of major adaptive responses to an unbalanced oxygen tension is central to understanding tissue homeostasis and disease. Hypoxia-inducible transcription factors (HIFs) coordinate changes in the transcriptome that control these adaptive responses. Here, we focused on the functional role of the transcriptional repressor basic-helix-loop-helix family member e40 (Bhlhe40), which we previously identified in a meta-analysis as one of the most consistently upregulated genes in response to hypoxia across various cell types. We investigated the role of Bhlhe40 in controlling proliferation and angiogenesis using a gene editing strategy in mouse embryonic stem cells (mESCs) that we differentiated in embryoid bodies (EBs). We observed that hypoxia-induced Bhlhe40 expression was compatible with the rapid proliferation of pluripotent mESCs under low oxygen tension. However, in EBs, hypoxia triggered a Bhlhe40-dependent cell cycle arrest in most progenitor cells and endothelial cells within vascular structures. Furthermore, Bhlhe40 knockout increased the basal vascularization of the EBs in normoxia and exacerbated the hypoxia-induced vascularization, supporting a novel role for Bhlhe40 as a negative regulator of blood vessel formation. Our findings implicate Bhlhe40 in mediating key functional adaptive responses to hypoxia, such as proliferation arrest and angiogenesis.

show abstract

Characterization of tumor-associated endothelial cells and the development of a prognostic model in pancreatic ductal adenocarcinoma

Cited by 3 publications

References 51 publications

Bhlhe40 limits proliferation and prevents excessive angiogenesis in mouse embryoid bodies under hypoxia

Bhlhe40 limits proliferation and prevents excessive angiogenesis in mouse embryoid bodies under hypoxia

Tumor Microenvironment Landscapes Supporting EGFR-mutant NSCLC Are Modulated at the Single-cell Interaction Level by Unesbulin Treatment

Bhlhe40 Regulates Proliferation and Angiogenesis in Mouse Embryoid Bodies under Hypoxia

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