Biology subjects

Gay, F.

Publications and source records attributed to Gay, F..

4 recordsLinked to original sources

bioRxiv2023

Single-cell transcriptomic analysis of NK cell dynamics in myeloma patients reveal persistent reduction of cytotoxic NK cells from diagnosis to relapse

Natural killer (NK) cells mediate the cytotoxic immune response against multiple myeloma and are important effector cells in immune therapies through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry and functional assays to investigate the bone marrow NK cell compartment of myeloma patients at diagnosis, during treatment and after relapse. The bone marrow of myeloma patients is characterized by a reduction in conventional cytotoxic NK cells that persists throughout treatment. We show in 20% of newly diagnosed myeloma patients that an altered balance between cytotoxic and cytokine-producing NK cells translates into a reduced cytotoxic ability in response to therapeutic antibodies. The relative loss of cytotoxic NK cells persists at relapse and is accompanied by an expansion of IFN-responsive NK cells. These findings reveal previously unappreciated alterations in bone marrow NK cell composition and highlight the importance of understanding the bone marrow immune system in patients receiving immunotherapies. Statement of significanceThe bone marrow of multiple myeloma patients is characterized by a persistent reduction in cytotoxic CD56dim NK cells, accompanied by inferior in vitro responses to therapeutic antibodies at diagnosis and an increase in IFN-responsive NK cells at relapse. These findings highlight the importance of understanding the BM microenvironment in multiple myeloma patients receiving immunotherapies.

immunology↗

bioRxiv2023

An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

The bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor-supportive, transcribing increased levels of IL-1{beta}, and myeloma cell survival factor BAFF. Interactions with inflammatory stromal cells can induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting treatment, patient bone marrow retains residual stromal inflammation and newly-formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.

immunology↗

bioRxiv2021

Modeling breast cancer by grafting patient tumor samples in the avian embryo: an in vivo platform for therapy evaluation coupled to large scale molecular analyses

Lack of preclinical patient-derived xenograft (PDX) cancer models in which to conduct large scale molecular studies seriously impairs the development of effective personalized therapies. We report here on an in vivo concept consisting of implanting human tumor cells in targeted tissues of an avian embryo, delivering therapeutics, evaluating their efficacy by measuring tumors using light sheet confocal microscopy, and conducting large scale RNAseq analysis to characterize therapeutic-induced changes in gene expression. The model was established to recapitulate triple negative breast cancer (TNBC) and validated using TNBC standards of care (SOCs) and an investigational therapeutic agent.

cancer biology↗

bioRxiv2020

HNRNPM controls circRNA biogenesis and splicing fidelity to sustain prostate cancer cell fitness

Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus represents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) cell growth, we performed a parallel pooled shRNA screen on in vitro passaged cells and in vivo xenografted PCa tumor lines. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP-sequencing data suggest that HNRNPM is bound to transcripts of key homeostatic genes and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In both linear and circular mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching antisense oligonucleotides (SSOs) was sufficient to inhibit cell growth in HNRNPM expressing cells. This suggests that prostate cancer cell dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Taken together, our data reveal a role for HNRNPM in supporting prostate cancer cell fitness, and also as a potential therapeutic target in PCa.

genomics↗