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5 results on '"Abdallah Gaballa"'

1. PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma

Author

Abdallah Gaballa, Anneli Gebhardt-Wolf, Bastian Krenz, Greta Mattavelli, Mara John, Giacomo Cossa, Silvia Andreani, Christina Schülein-Völk, Francisco Montesinos, Raphael Vidal, Carolin Kastner, Carsten P. Ade, Burkhard Kneitz, Georg Gasteiger, Peter Gallant, Mathias Rosenfeldt, Angela Riedel, and Martin Eilers

Subjects
Science
Abstract

Abstract In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

Published
2024
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2. MYC multimers shield stalled replication forks from RNA polymerase

Author

Daniel Solvie, Apoorva Baluapuri, Leonie Uhl, Daniel Fleischhauer, Theresa Endres, Dimitrios Papadopoulos, Amel Aziba, Abdallah Gaballa, Ivan Mikicic, Ekaterina Isaakova, Celeste Giansanti, Jennifer Jansen, Marvin Jungblut, Teresa Klein, Christina Schülein-Völk, Hans Maric, Sören Doose, Markus Sauer, Petra Beli, Andreas Rosenwald, Matthias Dobbelstein, Elmar Wolf, and Martin Eilers

Subjects
Binding Sites, Multidisciplinary, Transcription, Genetic, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Humans, DNA Breaks, Double-Stranded, DNA-Directed RNA Polymerases, RNA Polymerase II, RNA, Messenger, Promoter Regions, Genetic, Chromatin, S Phase
Abstract

Oncoproteins of the MYC family drive the development of numerous human tumours

Published
2022

3. Figure S1 from MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma

Author

Martin Eilers, Elmar Wolf, Lars Zender, Stefan Bauer, Mathias T. Rosenfeldt, Georg Gasteiger, Armin Wiegering, Luana D'Artista, Peter Gallant, Ursula Eilers, Apoorva Baluapuri, Emilia Vendelova, Florian Roehrig, Abdallah Gaballa, Carsten P. Ade, Anneli Gebhardt-Wolf, and Bastian Krenz

Abstract

Characterization of MYC function in KPC cells.

Published
2023

4. Data from MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma

Author

Martin Eilers, Elmar Wolf, Lars Zender, Stefan Bauer, Mathias T. Rosenfeldt, Georg Gasteiger, Armin Wiegering, Luana D'Artista, Peter Gallant, Ursula Eilers, Apoorva Baluapuri, Emilia Vendelova, Florian Roehrig, Abdallah Gaballa, Carsten P. Ade, Anneli Gebhardt-Wolf, and Bastian Krenz

Abstract

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC.Significance:This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.

Published
2023

5. MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma

Author

Lars Zender, Carsten P. Ade, Mathias T. Rosenfeldt, Emilia Vendelova, Ursula Eilers, Bastian Krenz, Elmar Wolf, Anneli Gebhardt-Wolf, Armin Wiegering, Peter Gallant, Abdallah Gaballa, Apoorva Baluapuri, Stefan Bauer, Florian Roehrig, Luana D’Artista, Georg Gasteiger, and Martin Eilers

Subjects
Cancer Research, Kruppel-Like Transcription Factors, Mice, Nude, Biology, Adenocarcinoma, Protein Serine-Threonine Kinases, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Paracrine signalling, Mice, 0302 clinical medicine, Immune system, TANK-binding kinase 1, Mice, Inbred NOD, MHC class I, Animals, Humans, Autocrine signalling, 030304 developmental biology, Immune Evasion, RNA, Double-Stranded, Cell Nucleus, 0303 health sciences, Mice, Inbred BALB C, RNA, Biological Transport, Sequence Analysis, DNA, Introns, Cell biology, Mice, Inbred C57BL, Pancreatic Neoplasms, RNA silencing, HEK293 Cells, Oncology, 030220 oncology & carcinogenesis, Immune System, TLR3, biology.protein, Tumor Suppressor Protein p53, Gene Deletion, Carcinoma, Pancreatic Ductal
Abstract

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. Significance: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.

Published
2021

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