Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence

Spencer S Watson ¹, Anoek Zomer ², Nadine Fournier ³, Joao Lourenco ³, Manfredo Quadroni ⁴, Agnieszka Chryplewicz ⁵, Sina Nassiri ³, Pauline Aubel ¹, Simona Avanthay ², Davide Croci ², Erik Abels ⁶, Marike L D Broekman ⁶, Douglas Hanahan ⁷, Jason T Huse ⁸, Roy T Daniel ⁹, Monika E Hegi ¹⁰, Krisztian Homicsko ¹¹, Giulia Cossu ¹², Andreas F Hottinger ¹³, Johanna A Joyce ¹⁴

. 2024 Sep 9;42(9):1507-1527.e11.

 doi: 10.1016/j.ccell.2024.08.012.

• PMID: 39255775
• DOI: 10.1016/j.ccell.2024.08.012

Free article

Abstract

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.

PPARs as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation Editorial

Manuel Vázquez-Carrera ^1 2 3 4, Walter Wahli ^5 6 7

Affiliations expand

• . 2024 Apr 18;25(8):4467.
• PMID: 38674052
• PMCID: PMC11050553
• DOI: 10.3390/ijms25084467

Abstract

The metabolic and immune systems are complex networks of organs, cells, and proteins that are involved in the extraction of energy from food; this is to run complex cellular processes and defend the body against infections while protecting its own tissues, respectively […].

Comprehensive map of ribosomal 2′-O-methylation and C/D box snoRNAs in Drosophila melanogaster

Athena Sklias ¹, Sonia Cruciani ², Virginie Marchand ³, Mariangela Spagnuolo ⁴, Guillaume Lavergne ¹, Valérie Bourguignon ³, Alessandro Brambilla ⁵, René Dreos ¹, Steven J Marygold ⁶, Eva Maria Novoa ^2 7, Yuri Motorin ³, Jean-Yves Roignant ^1 4

. 2024 Apr 12;52(6):2848-2864.

 doi: 10.1093/nar/gkae139.

• PMID: 38416577
• PMCID: PMC11014333
• DOI: 10.1093/nar/gkae139

Abstract

During their maturation, ribosomal RNAs (rRNAs) are decorated by hundreds of chemical modifications that participate in proper folding of rRNA secondary structures and therefore in ribosomal function. Along with pseudouridine, methylation of the 2′-hydroxyl ribose moiety (Nm) is the most abundant modification of rRNAs. The majority of Nm modifications in eukaryotes are placed by Fibrillarin, a conserved methyltransferase belonging to a ribonucleoprotein complex guided by C/D box small nucleolar RNAs (C/D box snoRNAs). These modifications impact interactions between rRNAs, tRNAs and mRNAs, and some are known to fine tune translation rates and efficiency. In this study, we built the first comprehensive map of Nm sites in Drosophila melanogaster rRNAs using two complementary approaches (RiboMethSeq and Nanopore direct RNA sequencing) and identified their corresponding C/D box snoRNAs by whole-transcriptome sequencing. We de novo identified 61 Nm sites, from which 55 are supported by both sequencing methods, we validated the expression of 106 C/D box snoRNAs and we predicted new or alternative rRNA Nm targets for 31 of them. Comparison of methylation level upon different stresses show only slight but specific variations, indicating that this modification is relatively stable in D. melanogaster. This study paves the way to investigate the impact of snoRNA-mediated 2′-O-methylation on translation and proteostasis in a whole organism.