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  • 1
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    Online Resource
    Abstract PR03: Metabolic control of Polycomb Repressive Complex 2 in Lung Disease and Lung Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 23_Supplement ( 2020-12-01), p. PR03-PR03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 23_Supplement ( 2020-12-01), p. PR03-PR03
    Abstract: Dysregulated epigenetic control of lung lineage fate is believed to be a major driver of lung disease, including plasticity in lung cancer. Our laboratory has observed a marked decrease in Polycomb Repressive Complex 2 (PRC2) activity in bronchiolar epithelium of COPD patients, poorly differentiated adenocarcinomas and the majority of squamous cell carcinomas. Interestingly, the PRC2 methyltransferase EZH2 is still highly expressed in many of these tissues, suggesting a de-coupling of EZH2 and PRC2 activity. A mouse model of lineage switching from adenocarcinoma to squamous lung cancer clearly showed that loss of PRC2 activity was a catalyst to epigenetic reprogramming. This model also showed increased infiltration of neutrophils, which are known to produce large amounts of superoxide. Our current hypothesis is that oxidative stress, in part through neutrophil recruitment to lung tissue, drives the loss of PRC2 activity through metabolic changes. To support this hypothesis, we have shown that a redox-sensitive enzyme in the methionine pathway, cystathionine beta synthase (CBS), is expressed in COPD and lung cancer and modulates PRC2 activity. Enforced CBS expression drives global decrease in the PRC2-mediated histone marked, H3K27me3, and increased expression of genes expressed by basal cells of the lung, including KRT5, SOX2 and PD-L1. Furthermore, we have found that PRC2 activity can be stabilized through restriction of methionine levels or knock-down of CBS, leading to increased sensitivity of cells to chemotherapy and radiation treatments. PRC2-low epigenetic states can also be exploited – either pharmacological or genetic perturbation of EZH2 led to sensitivity to several classes of drugs, including immunotherapies. Our future studies include using Stable Isotope Resolved Metabolomics (SIRM) to understand how oxidative stress alters the methionine cycle and ultimately changes the stability and function of the PRC2 complex, and to use this information to design better therapeutic strategies. Work supported by AACR Innovation and Discovery Grant, American Cancer Society 133123-RSG-19-081-01-TBG and IRG-85-001-25, NCI R01 CA237643, NIGMS P20 GM121327-03, NIEHS T32 5T32ES007266-30, NCI T32 CA165990 and NHLBI F31 HL151111-01. Citation Format: Mojtaba Bakhtiari, Aria L. Byrd, Fan Chen, Alexsandr Lukyanchuk, Tanner J. DuCote, Christine Fillmore Brainson. Metabolic control of Polycomb Repressive Complex 2 in Lung Disease and Lung Cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.EPIMETAB20-PR03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Online Resource
    Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate
    Elsevier BV ; 2023
    In:  Stem Cell Reports Vol. 18, No. 1 ( 2023-01), p. 289-304
    Details
    In: Stem Cell Reports, Elsevier BV, Vol. 18, No. 1 ( 2023-01), p. 289-304
    Type of Medium: Online Resource
    ISSN: 2213-6711
    URL: Article
    DOI: 10.1016/j.stemcr.2022.11.009
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 3
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    Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors
    Springer Science and Business Media LLC ; 2023
    In:  Nature Communications Vol. 14, No. 1 ( 2023-01-20)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-01-20)
    Abstract: Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 could be suppressed by BET inhibition. Poorly differentiated human lung cancers were enriched for an H3K27me3-low state, representing a subtype that may benefit from BET inhibition as a single therapy or combined with additional EZH2 inhibition. These data highlight diverse roles of PRC2 in KRAS-driven lung adenocarcinomas, and demonstrate the utility of three-dimensional cultures for exploring epigenetic drug sensitivities for cancer.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-023-35784-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 4
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    Abstract 2363: Targeting squamous lung tumor heterogeneity with EZH2 inhibition to improve immunotherapy responses
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2363-2363
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2363-2363
    Abstract: Immunotherapies, including those targeting the PD1/PD-L1 immune checkpoint, have become popular treatment options, but they are effective for only 20% of squamous lung cancer patients. Work in our laboratory has suggested that inhibition of the histone methyltransferase EZH2 drives a basal-like transcriptional state which includes expression of the immunotherapy target PD-L1, and work from others has demonstrated that EZH2 inhibition could influence the tumor microenvironment. Therefore, we hypothesize that combining EZH2 inhibition with anti-PD1 therapy could boost response in squamous lung cancers by targeting both the tumor and the microenvironmental heterogeneity. Our laboratory uses genetically engineered mouse models of lung cancer and patient-derived cell lines and organoids to dissect the mechanistic effects of EZH2 inhibition on tumor cells and immune cells. First, we treated a panel of squamous and adeno-squamous human NSCLC cell lines with EZH2 inhibition and observed increased expression of PD-L1 and another basal cell marker, NGFR, by flow cytometry. Similar results were obtained by treating two patient-derived organoids of squamous lung cancer with EZH2 inhibitor, suggesting that EZH2 inhibition drives squamous tumor cells into a more basal-like state which may be more susceptible to anti-PD1 immunotherapy. In our mouse models of squamous lung cancer, we noted abundant tumor-associated neutrophils, which we believe may be inhibiting efficacy of immunotherapy by suppressing CD8 T cell function. In support of the idea that inhibiting EZH2 will ameliorate this phenotype, lung neutrophils isolated from EZH2 conditional knock-out mice had significantly lower levels of the T cell suppressive protein Arginase 1 than WT lung neutrophils or Lkb1/Pten TANs. Lastly, we treated mice harboring autochthonous squamous lung tumors with EZH2 inhibitor, and observed a striking increase in the proportion of tumor cells expressing PD-L1 but now defect in tumor growth. In contrast, two squamous lung tumor bearing mice treated with EZH2 inhibitor and anti-PD-1 immunotherapy had tumor regression that was durable up to 4 weeks post-treatment initiation. We plan to expand the cohorts of mice and test this promising combination therapy in a variety of lung cancer mouse models. Completion of these studies will solidify the efficacy of a promising therapeutic combination and uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2 inhibitors in squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibition with anti-PDL1 just began recruiting late stage non-small cell lung cancer patients, learning the phenotypes and mechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue. Funded by V Foundation Scholar Award, K22 CA201036 and KY LCRP to CFB Citation Format: Tanner J. DuCote, Christine Fillmore Brainson. Targeting squamous lung tumor heterogeneity with EZH2 inhibition to improve immunotherapy responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2363.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2363
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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