Slim Mzoughi

Icahn School of Medicine at Mount Sinai

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Ernesto Guccione

Icahn School of Medicine at Mount Sinai

Megan Schwarz

Icahn School of Medicine at Mount Sinai

Diana Low

Institute of Molecular and Cell Biology

Federico Di Tullio

Icahn School of Medicine at Mount Sinai

Heike Wollmann

Agency for Science, Technology and Research

Kevin Mohammed

Icahn School of Medicine at Mount Sinai

Denis Torre

Icahn School of Medicine at Mount Sinai

Dan Hasson

Icahn School of Medicine at Mount Sinai

Daniel Lozano‐Ojalvo

Icahn School of Medicine at Mount Sinai

N. Ray Dunn

Nanyang Technological University

Cooperative Institutions

Icahn School of Medicine at Mount Sinai

Agency for Science, Technology and Research

Institute of Molecular and Cell Biology

National University of Singapore

Harvard University

Boston Children's Hospital

Institute of Medical Biology

McGill University

Rockefeller University

Duke-NUS Medical School

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Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

Nature Genetics (2025)

Slim Mzoughi Megan Schwarz Xuedi Wang Deniz Demircioğlu Gulay Ulukaya

Reprogramming

Beta-catenin

10.1038/s41588-024-02058-1

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Citations (0)

Les récepteurs aux androgènes dans le cancer du sein : expression, valeur et perspectives thérapeutiques

Bulletin du Cancer (2017)

Delphine Héquet Slim Mzoughi Roman Rouzier Ernesto Guccione

10.1016/j.bulcan.2017.01.005

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Citations (4)

Cancer synthetic vulnerabilities to protein arginine methyltransferase inhibitors

Current Opinion in Pharmacology (2021)

Ernesto Guccione Megan Schwarz Federico Di Tullio Slim Mzoughi

Transcription

10.1016/j.coph.2021.04.004

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Citations (17)

The role of PRDMs in cancer: one family, two sides

Current Opinion in Genetics & Development (2016)

Slim Mzoughi Ying Xim Tan Diana Low Ernesto Guccione

Protein family

10.1016/j.gde.2016.03.009

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Citations (85)

Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation

Molecular Cell (2023)

Denis Torre Yesai Fstkchyan Jessica Ho Youngseo Cheon Roosheel S. Patel

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Endogenous retrovirus

Transcription

Euchromatin

10.1016/j.molcel.2023.10.036

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T cell immunity is key to the pandemic endgame: How to measure and monitor it

Current Research in Immunology (2022)

Megan Schwarz Slim Mzoughi Daniel Lozano‐Ojalvo Anthony T. Tan Antonio Bertoletti

As vaccine deployment improves the healthcare emergency status caused by the SARS-CoV-2 pandemic, we need reliable tools to evaluate the duration of protective immunity at a global scale. Seminal studies have demonstrated that while neutralizing antibodies can protect us from viral infection, T cell-mediated cellular immunity provides long-term protection from severe COVID-19, even in the case of emerging new variants of concern (VOC). Indeed, the emergence of VOCs, able to substantially escape antibodies generated by current vaccines, has made the analysis of correlates of humoral protection against infection obsolete. The focus should now shift towards immunological correlates of protection from disease based on quantification of cellular immunity. Despite this evidence, an assessment of T cell responses is still overlooked. This is largely due to technical challenges and lack of validated diagnostic tests. Here, we review the current state of the art of available tests to distinguish between SARS-CoV-2 antigen-specific Tcells and non-antigen specific T-cells. These assays range from the analysis of the T cell-receptor (TCR) diversity (i.e. Immunoseq and MHC tetramer staining) to the detection of functional T cell activation (i.e. ICS, AIM, Elispot, ELLA, dqTACT, etc.) either from purified Peripheral Blood Mononuclear Cells (PBMCs) or whole blood. We discuss advantages and disadvantages of each assay, proposing their ideal use for different scopes. Finally, we argue how it is paramount to deploy cheap, standardized, and scalable assays to measure T cell functionality to fill this critical diagnostic gap and manage these next years of the pandemic.

ELISPOT

Pandemic

10.1016/j.crimmu.2022.08.004

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Citations (26)

WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma

Nature Cancer (2023)

Alexander Rialdi Mary E. Duffy Alex P. Scopton Frank Fonseca Julia N. Zhao

10.1038/s43018-023-00609-9

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PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

Nature Communications (2020)

Slim Mzoughi Jia Yi Fong David Papadopoli Cheryl M. Koh Laura Hulea

Abstract PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.

Cell metabolism

10.1038/s41467-020-17064-0

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Citations (29)

A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Slim Mzoughi Megan Schwarz Xuedi Wang Deniz Demircioğlu Gulay Ulukaya

Summary Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment 1 . However, the molecular mechanisms underlying resistance to LGR5 + CSCs depletion in colorectal cancer (CRC) 2,3 remain largely elusive. Here, we unveil the existence of a primitive cell state dubbed the oncofetal (OnF) state, which works in tandem with the LGR5 + stem cells (SCs) to fuel tumor evolution in CRC. OnF cells emerge early during intestinal tumorigenesis and exhibit features of lineage plasticity. Normally suppressed by the Retinoid X Receptor (RXR) in mature SCs, the OnF program is triggered by genetic deletion of the gatekeeper APC. We demonstrate that diminished RXR activity unlocks an epigenetic circuity governed by the cooperative action of YAP and AP1, leading to OnF reprogramming. This high-plasticity state is inherently resistant to conventional chemotherapies and its adoption by LGR5 + CSCs enables them to enter a drug-tolerant state. Furthermore, through phenotypic tracing and ablation experiments, we uncover a functional redundancy between the OnF and stem cell (SC) states and show that targeting both cellular states is essential for sustained tumor regression in vivo . Collectively, these findings establish a mechanistic foundation for developing effective combination therapies with enduring impact on CRC treatment.

LGR5

Reprogramming

10.1101/2023.12.10.570854

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Citations (1)

p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6

Nucleic Acids Research (2012)

Sameer Phalke Slim Mzoughi Marco Bezzi Nancy Jennifer Wei Chuen Mok

p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence. Consistent with this role, p21 is a downstream target of several tumour suppressors and oncogenes, and it is downregulated in the majority of tumours, including breast cancer. Here, we report that protein arginine methyltransferase 6 (PRMT6), a type I PRMT known to act as a transcriptional cofactor, directly represses the p21 promoter. PRMT6 knock-down (KD) results in a p21 derepression in breast cancer cells, which is p53-independent, and leads to cell cycle arrest, cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency (SCID) mice for all the cancer lines examined. We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence, and it restores their ability to grow on soft agar. We conclude that PRMT6 acts as an oncogene in breast cancer cells, promoting growth and preventing senescence, making it an attractive target for cancer therapy.

Senescence

10.1093/nar/gks858

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Citations (93)