Giacomo Cossa

University of Würzburg

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Paola Perego

Fondazione IRCCS Istituto Nazionale dei Tumori

Laura Gatti

Center for Sustainable Future Technologies

Nadia Zaffaroni

Fondazione IRCCS Istituto Nazionale dei Tumori

Martin Eilers

University of Würzburg

Franco Zunino

University of California, Berkeley

Cinzia Lanzi

Fondazione IRCCS Istituto Nazionale dei Tumori

Giuliana Cassinelli

Fondazione IRCCS Istituto Nazionale dei Tumori

Giovanni Luca Beretta

Fondazione IRCCS Istituto Nazionale dei Tumori

Carsten P. Ade

University of Würzburg

Nives Carenini

Fondazione IRCCS Istituto Nazionale dei Tumori

Cooperative Institutions

Fondazione IRCCS Istituto Nazionale dei Tumori

University of Milan

University of Würzburg

Universitätsklinikum Würzburg

Istituti di Ricovero e Cura a Carattere Scientifico

Comprehensive Cancer Center Mainfranken

University of Milano-Bicocca

University of Tübingen

Heidelberg University

Ludwig-Maximilians-Universität München

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Novel Insights into Targeting ATP-Binding Cassette Transporters for Antitumor Therapy

Current Medicinal Chemistry (2011)

Laura Gatti Giacomo Cossa Giovanni Luca Beretta Nadia Zaffaroni Paola Perego

ATP-binding cassette (ABC) transporters are a large family of proteins implicated in physiological cellular functions. Selected components of the family play a well-recognized role in extruding conventional cytotoxic antitumor agents and molecularly targeted drugs from cells. Some lines of evidence also suggest links between transporters and tumor cell survival, in part unrelated to efflux. However, the study of the precise mechanisms regulating the function of drug transporters (e.g., posttranslational modifications such as glycosylation) is still in its infancy. A better definition of the molecular events clarifying the regulation of transporter levels including regulation by microRNAs may contribute to provide new molecular tools to target such a family of transporters. The present review focuses on the biological aspects that implicate ABC transporters in resistance of tumor cells, including cancer stem cells. Molecular analysis of well-known preclinical systems as well as of cancer stem cell models supports the notion that ABC transporters represent amenable targets for modulation of the efficacy of antitumor agents endowed with different molecular features. Recent achievements regarding tumor cell biology are expected to provide a rationale for developing novel inhibitors that target ABC transporters implicated in drug resistance.

Abcg2

Efflux

Solute carrier family

Multidrug Resistance-Associated Proteins

10.2174/092986711797189682

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Citations (31)

Localized Inhibition of Protein Phosphatase 1 by NUAK1 Promotes Spliceosome Activity and Reveals a MYC-Sensitive Feedback Control of Transcription

Molecular Cell (2020)

Giacomo Cossa Isabelle Roeschert Florian Prinz Apoorva Baluapuri Raphael Vidal

Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes.

Spliceosome

RNA polymerase II

Transcription

Protein phosphatase 1

10.1016/j.molcel.2020.01.008

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Citations (50)

Modulation of cell sensitivity to antitumor agents by targeting survival pathways

Biochemical Pharmacology (2010)

Paola Perego Giacomo Cossa Valentina Zuco Franco Zunino

10.1016/j.bcp.2010.07.030

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Citations (16)

Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway

Current Pharmaceutical Design (2012)

Giacomo Cossa Laura Gatti Giuliana Cassinelli Cinzia Lanzi Nadia Zaffaroni

Modulation (music)

10.2174/138161213804547187

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Citations (46)

RNA-mediated MYC multimerization suppresses innate immune signaling

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Leonie Uhl Amel Aziba Sinah Loebbert Timothy J. Russell Toshitha Kannan

In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition; the underlying mechanisms and their function are unknown. Here, we show that MYC re-localizes from its canonical location on DNA to RNA in response to the accumulation of intronic RNA. MYC binds RNA directly, which enhances its multimerization. MYC multimers concentrate the nuclear exosome, a 3'-5' RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops, and promote exosome recruitment to R-loops. RNA binding of MYC suppresses activation of the innate immune kinase TBK1. Upon MYC depletion, intron-derived dsRNAs, including RNA derived from repetitive elements and small nucleolar RNAs, accumulate on TLR3, a pattern recognition receptor that activates TBK1. In MYC-depleted cells, TLR3-bound snoRNAs carry aberrant 3'-ends, indicating defective exosomal processing. Our data show that the phase transition of MYC is a RNA-driven stress response that suppresses the accumulation of immunogenic RNAs.

10.1101/2024.12.06.627168

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Nucleolar detention of NONO shields DNA double-strand breaks from aberrant transcripts

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Barbara Trifault Victoria Mamontova Giacomo Cossa Sabina Ganskih Yuanjie Wei

ABSTRACT RNA-binding proteins (RBPs) stimulate the DNA damage response (DDR). The RBP NONO marks nuclear paraspeckles in unperturbed cells and undergoes poorly understood re-localisation to the nucleolus upon induction of DNA double-strand breaks (DSBs). Here we show that treatment with the topoisomerase-II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-induced nucleolar antisense RNAs (diNARs) in human cells. diNARs originate from the nucleolar intergenic spacer and tether NONO to the nucleolus via its RRM1 domain. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signaling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.

10.1101/2023.07.14.548979

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Citations (2)

Abstract 1257: A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer

Cancer Research (2016)

Daniel Dauch Ramona Rudalska Giacomo Cossa Jean‐Charles Nault Sandrine Imbeaud

Abstract Myc oncoproteins are causally involved in the genesis of a large fraction of human tumors. Three closely related Myc proteins, c-myc, N-myc and L-myc, have been implicated in cancer, whereas c-myc was identified as an important oncogenic driver in frequent solid tumors.Applying transposon-based mosaic liver cancer mouse models and direct in vivo shRNA screening technology, we found that bypassing a latent p19Arf- and Aurka mediated G2/M cell cycle arrest is required for development of p53 altered liver carcinomas with activated Ras/MAPK signalling. The resulting tumors depend on high MYC levels for survival. A direct interaction of Aurka and MYC was identified in p53 altered liver cancer cells, which could be efficiently disrupted by conformation changing Aurka inhibitors, resulting in MYC degradation and cell death specifically of p53 altered human and murine hepatoma cells. Treatment studies in mouse models of p53 deficient therapy resistant liver cancer revealed marked therapeutic efficacy of conformation changing Aurka inhibitors, thus suggesting a new therapeutic strategy against this major lethal cancer. Citation Format: Dauch Daniel, Ramona Rudalska, Giacomo Cossa, Jean Charles Nault, Sandrine Imbeaud, Nisar P. Malek, Thomas Longerich, Stefan Laufer, Antti Poso, Jessica Zucman-Rossi, Martin Eilers, Lars Zender. A MYC-Aurka protein complex represents an actionable target in p53 altered liver cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1257.

Liver Cancer

10.1158/1538-7445.am2016-1257

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Citations (0)

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

Nature Communications (2024)

Abdallah Gaballa Anneli Gebhardt-Wolf Bastian Krenz Greta Mattavelli Mara John

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.

RNA polymerase II

Transcription

Tumor progression

10.1038/s41467-024-45760-8

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Citations (3)

Role of tyrosyl-DNA phosphodiesterase 1 and inter-players in regulation of tumor cell sensitivity to topoisomerase I inhibition

Biochemical Pharmacology (2011)

Paola Perego Giacomo Cossa Stella Tinelli Elisabetta Corna Nives Carenini

Camptothecin

PARP1

XRCC1

Topoisomerase inhibitor

10.1016/j.bcp.2011.09.021

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Citations (42)

Abstract A59: Increased expression of ABC transporter genes in lung cancer CD133-positive cells

Molecular Cancer Therapeutics (2009)

Laura Gatti Giacomo Cossa Giulia Bertolini Monica Tortoreto Stella Tinelli

Abstract Drug resistance represents a major obstacle towards the cure of different tumor types including non-small cell lung cancer (NSCLC), being one of the main causes of failure of antitumor therapy. Tumor cells frequently exhibit simultaneous resistance to multiple structurally unrelated drugs, a phenotype known as multidrug resistance (MDR). A major cause of the MDR phenotype is the over-expression of members of a conserved family of transmembrane proteins (ABC transporters). Different structurally unrelated compounds, including conventional cytotoxic and target-specific agents are substrates for ABC transporters. Cancer stem cells (CSC) refer to a subset of tumor cells with the ability to self-renew and generate the diverse cells that comprise tumors. At present, the mechanisms contributing to the drug-resistant phenotype of CSC are poorly understood. Some lines of evidence support that specific ABC transporters may be expressed in CSC and may be relevant therapeutic targets. The aim of the present study was to examine the pattern of expression of ABC transporter genes in spheres derived from human lung tumors, which we found enriched for CD133 (prominin-1), a surface glycoprotein described as a marker of cancer-initiating cells in different tumor types. To better define the molecular features of cancer cells endowed with stem-like features with respect to cellular defence mechanisms, using TaqMan MicroFluidic cards we analyzed the mRNA levels of transporters of the ABC superfamily in CD133+ and CD133− cell populations sorted from lung tumor cell lines grown as spheres. With this approach, we found that around 70% of the 50 human ABC transporters were expressed at detectable levels in floating spheres obtained from human lung cancer A549 adherent cell line and in the corresponding sorted populations. When compared to the CD133− raction, CD133+ cells exhibited a marked increased expression of different components of the ABCC family which are known to be involved in the MDR phenotype (i.e., ABCC1). The level of ABCG2 mRNA was also enhanced. Similar results were obtained in CD133+ cells isolated from a cell line established from a human primary lung tumor growing as floating spheres. Thus, CD133+ cells expressed ABCG2 and additional ABC transporters that may contribute to determine a drug-resistant phenotype. A better knowledge of the pattern of expression of ABC transporters in lung cancer CD133+ cells may lead to develop approaches that will circumvent drug resistance in NSCLC and is expected to contribute to optimization of therapy, based on targeting of ABC transporters. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A59.

10.1158/1535-7163.targ-09-a59

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