Biology subjects

Maggi, L. B.

Publications and source records attributed to Maggi, L. B..

3 recordsLinked to original sources

bioRxiv2026

Hypoxic stress granules trigger immunogenic dormancy in lung cancer

Induction of the MHC class I antigen processing and presentation pathway (C1APP) is a critical part of the IFN-{gamma} response necessary for effective cytotoxic immunity against tumors of epithelial origin1,2. Loss of this response is associated with worse disease outcomes and renders patients refractory to immunotherapies3-6. Without C1APP induction, tumor cells cannot optimally process and present immunopeptides from tumor-associated antigens (TAA) and neoantigens to effector cytotoxic T cells7-9. Here, we show that physiologic levels of hypoxia block induction of the immunoproteasome (IP) and other C1APP components in cancer cells, including human non-small cell lung cancer (NSCLC). In A549 cells, this leads to impaired presentation of more than 73% of detectable immunopeptides, including TAA and neoantigen-derived immunopeptides. This effect is independent of HIF-1 or HIF-2 signaling, protein degradation, autophagy, or stimulus type. Instead, hypoxia induces translational arrest of C1APP mRNAs prior to complete monosome loading, along with sequestration into hypoxia-associated stress granules. This phenomenon is reversible with the epitranscriptomic compound 5-azacytidine. Consistent with these findings, IP expression is excluded from hypoxic regions in most human NSCLC tumors. Together, these results link tumor hypoxia to a state of "immunogenic dormancy" and identify stress granules as a previously unrecognized mechanism of immune escape.

cancer biology↗

bioRxiv2025

Reconstructed Cell-Type Specific Rhythms in Human Brain link Alzheimer's Pathology, Circadian Stress, and Ribosomal Disruption

Alzheimers disease (AD) disrupts behavioral circadian rhythms, but its effects on molecular rhythms in the human brain are poorly understood. Using single-nucleus RNA sequencing from post-mortem cortical samples, we informatically estimated the relative circadian phases of 409 persons with and without AD dementia. We then reconstructed circadian expression profiles across cell types. While core clock rhythms were preserved in AD, many cell-type specific circadian outputs were disrupted. Rhythms in ribosomal biogenesis and oxidative phosphorylation were dampened across cell types. Similar losses in ribosomal gene expression rhythms were observed in APP/PS1 mice, which showed further reductions in ribosomal protein expression and polysome-mediated translation after circadian desynchrony. Exploratory computational modeling reveals that altered translation may contribute to the increased circadian variability seen in AD patients. These findings reveal altered cell-type specific circadian output rhythms in the brains of AD affected patients, and highlight disrupted ribosomal rhythms as a feature of AD.

bioinformatics↗

bioRxiv2024

Elevated type I interferon signaling defines the proliferative advantage of ARF and p53 mutant tumor cells

The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massive gains in cell proliferation and transformation and is often observed in some of the most aggressive human cancer subtypes. These phenotypic gains are preceded by increased type I interferon (IFN) signaling that involves canonical STAT1 activation and a subsequent IFN-stimulated gene (ISG) signature. Here, we show that cells lacking p53 and ARF require active JAK1 to phosphorylate STAT1 on Y701 to maintain their high rate of proliferation. In fact, the use of selective JAK1 inhibitors ruxolitinib or baricitinib inhibited the induction of ISGs and the proliferation of p53 and ARF deleted cells. We identify a group of solid human tumors that lack functional p53 and ARF, show an expression signature of the upregulated type I IFN response genes, and are sensitive to selective JAK1 inhibitors. These data suggest that the type I IFN response acts as a positive driver of proliferation in the absence of p53 and ARF and, as such, presents itself as a potential therapeutic target in aggressive solid tumors.

cancer biology↗