Biology subjects

McCortney, K.

Publications and source records attributed to McCortney, K..

4 recordsLinked to original sources

bioRxiv2022

The MIF SNP rs755622 is a germline determinant of tumor immune activation in Glioblastoma

While immunotherapies have shown durable responses for multiple tumors, their efficacy remains limited in some advanced cancers, including glioblastoma. This may be due to differences in the immune landscape, as the glioblastoma microenvironment strongly favors immunosuppressive myeloid cells, which are linked to an elevation in immune-suppressive cytokines, including macrophage migration inhibitory factor (MIF). We now find that a single-nucleotide polymorphism (SNP) rs755622 in the MIF promoter associates with increased leukocyte infiltration in glioblastoma. Furthermore, we identified lactotransferrin expression as being associated with the rs755622 SNP, which could also be used as a biomarker for immune infiltrated tumors. These findings provide the first example in glioblastoma of a germline SNP that underlies differences in the immune microenvironment and identifies high lactotransferrin as a potential factor promoting immune activation.

cancer biology↗

bioRxiv2021

SerpinB3 drives cancer stem cell survival in glioblastoma

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC therapeutic resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. The knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. Mechanistically, SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown dramatically increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of standard-of-care GBM therapies against therapeutically resistant CSCs. SummaryLauko et al. demonstrate a functional role for SerpinB3, which is elevated in glioblastoma cancer stem cells and protects against lysosomal-mediated cell death. SerpinB3 can be targeted to increase the efficacy of radiation in glioblastoma pre-clinical models.

cancer biology↗

bioRxiv2021

The efficacy of a ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma

Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1) or, less commonly, IDH2 (together called "IDHmut"). These mutations alter cellular biochemistry, and IDHmut gliomas are generally less aggressive than IDH wild-type (IDHwt) gliomas. Some preclinical studies and clinical trials have suggested that a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, not all studies have shown promising results, and to date, no study has addressed whether IDHmut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD in preclinical models of IDHwt versus IDHmut gliomas. In vitro, simulating KD by treatment with the ketone body {beta}-hydroxybutyrate had no effect on the proliferation of patient-derived IDHwt or IDHmut glioma cells. Likewise, a cycling KD, wherein mice alternated between KD and a standard diet (SD), had no effect on the in vivo growth of patient-derived IDHwt or IDHmut gliomas, even though the cycling KD did result in persistently elevated circulating ketones. Furthermore, KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDHmut glioma. These data suggest that neither IDHwt nor IDHmut gliomas are particularly responsive to KD.

cancer biology↗

bioRxiv2021

CRISPR-Cas9 Screen Reveals PSMB3 Contributes to Gliomagenesis Through Proteasome-Dependent and Independent Mechanisms

Glioblastoma (GBM) is the most common adult malignant brain tumor, with a median survival of 21 months and a 100% recurrence rate. Even though many of the critical oncogenic drivers for GBM have been identified, the basis of gliomagenesis is still under investigation. To identify novel genes that contribute to GBM progression, we performed a genome-wide CRISPR-Cas9 knockout screen. We identified four previously unstudied genes - PSMB3, CHCHD4, SPDYE5, HSPA1 - which had elevated expression in cancer and demonstrated a significant positive correlation with respect to GBM growth and patient survival in vivo and patient datasets. Furthermore, overexpression of PSMB3 and HSPA5 in neural stem cells resulted in transformation to a cancer phenotype. Further investigation of PSMB3, a subunit of the proteasome, allowed us to identify both ubiquitin-mediated and non-ubiquitin-mediated mechanisms of oncogenesis. Ultimately, the data from our CRISPR screens suggests that these genes drive tumor progression, making them promising therapeutic targets for GBM.

cancer biology↗