LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 2 of total 2

Search options

  1. Article: HIF2 Regulates Intestinal Wnt5a Expression.

    García García, Carolina J / Acevedo Diaz, Ariana C / Kumari, Neeraj / Govindaraju, Suman / de la Cruz Bonilla, Marimar / San Lucas, F Anthony / Nguyen, Nicholas D / Jiménez Sacarello, Iancarlos / Piwnica-Worms, Helen / Maitra, Anirban / Taniguchi, Cullen M

    Frontiers in oncology

    2021  Volume 11, Page(s) 769385

    Abstract: Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that ... ...

    Abstract Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs). Our group has previously shown that stabilization of HIF2 through genetic deletion or pharmacologic inhibition of the EGLNs mitigates and protects against GI radiotoxicity in mice by improving intestinal crypt stem cell survival. Here we aimed to elucidate the molecular mechanisms by which HIF2 confers GI radioprotection. We developed duodenal organoids from mice, transiently overexpressed non-degradable HIF2, and performed bulk RNA sequencing. Interestingly, HIF2 upregulated known radiation modulators and genes involved in GI homeostasis, including
    Language English
    Publishing date 2021-11-25
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2021.769385
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  2. Article ; Online: Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.

    Garcia Garcia, Carolina J / Huang, Yanqing / Fuentes, Natividad R / Turner, Madeleine C / Monberg, Maria E / Lin, Daniel / Nguyen, Nicholas D / Fujimoto, Tara N / Zhao, Jun / Lee, Jaewon J / Bernard, Vincent / Yu, Meifang / Delahoussaye, Abagail M / Jimenez Sacarello, Iancarlos / Caggiano, Emily G / Phan, Jae L / Deorukhkar, Amit / Molkentine, Jessica M / Saur, Dieter /
    Maitra, Anirban / Taniguchi, Cullen M

    Gastroenterology

    2022  Volume 162, Issue 7, Page(s) 2018–2031

    Abstract: Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, ...

    Abstract Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown.
    Methods: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade.
    Results: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models.
    Conclusions: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
    MeSH term(s) Animals ; Cancer-Associated Fibroblasts/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Humans ; Hypoxia/metabolism ; Immune Checkpoint Inhibitors ; Immunosuppression Therapy ; Mice ; Pancreatic Neoplasms/pathology ; Tumor Microenvironment ; Pancreatic Neoplasms
    Chemical Substances Immune Checkpoint Inhibitors
    Language English
    Publishing date 2022-02-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2022.02.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

To top