publications

2025

1. Biological research on mental pain, social pain and other pains not primarily felt in the body: methodological systematic review

   Etienne K. Duranté, Alexandre Ribeiro, Lucie Gaspard-Boulinc, and 6 more authors

   The British Journal of Psychiatry, Mar 2025

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   BackgroundResearchers explore the biology of painful experiences not primarily felt in the body (‘non-physical pain’), sometimes referred to as mental, social or emotional pain. A critical challenge lies in how to operationalise this subjective experience for biological research, a crucial process for translating findings into clinical practice.AimsTo map studies investigating biological features of non-physical pain, focusing on their conceptual features (i.e. terms and definitions of non-physical pain) and methodological characteristics (e.g. experimental paradigms and measures).MethodThis methodological systematic review searched reports of primary research on the biological features of non-physical pain across Embase, MEDLINE and Web of Science. Using a meta-research approach, we synthetised results on terms, definitions, populations, experimental paradigms, confounders, measures of non-physical pain and investigation methods (e.g. functional magnetic resonance imaging).ResultsWe identified 92 human studies, involving 7778 participants. Overall, 59.1% of the studies did not report any definition of non-physical pain, and 82% of studies did not use a specific measure. Regarding the possibility of translating results to clinical settings, most of the human studies involved only healthy participants (71.7%) and the seven different experimental paradigms used to induce non-physical pain had unknown external validity. Confounders were not considered by 32.4% of the experimental studies. Animal studies were rare, with only four rodent studies.ConclusionsBiomedical studies of non-physical pain use heterogeneous concepts with unclear overlaps and methods with unknown external validity. As has been done for physical pain, priority actions include establishing an agreed definition and measurement of non-physical pain and developing experimental paradigms with good external validity.

2024

1. Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML

   Nunki Hassan, Hangyu Yi, Bilal Malik, and 19 more authors

   Blood, Jul 2024

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   The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely because of the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor growth arrest and DNA damage-inducible 45 alpha (GADD45A) is implicated in poor clinical outcomes, but its role in LSCs and AML pathogenesis is unknown. Here, we define GADD45A as a key downstream target of G protein-coupled receptor (LGR)4 pathway and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia. Knockout of GADD45A enhances AML progression in murine and patient-derived xenograft (PDX) mouse models. Deletion of GADD45A induces substantial mutations, increases LSC self-renewal and stemness in vivo, and reduces levels of reactive oxygen species (ROS), accompanied by a decreased response to ROS-associated genotoxic agents (eg, ferroptosis inducer RSL3) and acquisition of an increasingly aggressive phenotype on serial transplantation in mice. Our single-cell cellular indexing of transcriptomes and epitopes by sequencing analysis on patient-derived LSCs in PDX mice and subsequent functional studies in murine LSCs and primary AML patient cells show that loss of GADD45A is associated with resistance to ferroptosis (an iron-dependent oxidative cell death caused by ROS accumulation) through aberrant activation of antioxidant pathways related to iron and ROS detoxification, such as FTH1 and PRDX1, upregulation of which correlates with unfavorable outcomes in patients with AML. These results reveal a therapy resistance mechanism contributing to poor prognosis and support a role for GADD45A loss as a critical step for leukemia-initiating activity and as a target to overcome resistance in aggressive leukemia.

2. The biology of mental pain: a systematic review to map the different expressions, definitions, hypotheses, experimental paradigms, investigation methods and candidate biomarkers of mental pain in human subjects

   E. K. Duranté, A. Ribeiro, L. Gaspard-Boulinc, and 3 more authors

   European Psychiatry, Apr 2024

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   IntroductionMental pain is a transdiagnostic symptom, predictive of suicide and reported as a critical outcome by patients. A previous systematic review of epidemiological and clinical research has shown a lack of consensual definition of mental pain in clinical research and high heterogeneity across the different measurement instruments of mental pain. Up today there is no systematic review synthetizing all published biological investigations on mental pain.ObjectivesThis study aims to map the field of biological investigations of mental pain in human to identify what and how biomarkers are investigated with a meta-research approach, by providing a critical appraisal of the terms and definitions of mental pain, the studies’ hypotheses, the experimental paradigms used to induce or mimic mental pain and the measurement instruments used to measure mental pain.MethodsWe conducted a systematic review (compliant with PRISMA guidelines) of all primary research reporting to investigate candidate biomarkers of mental pain in human subjects as stated by the authors. We searched from inception to June 23rd, 2022, the 3 databases MEDLINE, Web of Science and EMBASE. We extracted the study characteristics (e.g., year of publication, population, etc.), the terms used for meaning mental pain, the definition of mental pain, the method to induce mental pain and its rational, the hypotheses and aims, the measurement instruments of mental pain, the candidate biomarkers, and their method of investigation. We performed descriptive statistics of the sample’s characteristics and the extracted data, a qualitative analysis of the definitions, hypothesis, aims and experimental paradigms, and a data visualization linking candidate biomarkers, experimental paradigms, and their investigation methods.ResultsThe search retrieved 5685 papers of which we included 72 primary research publications constituting 78 distinct research studies. Only 37.5% of studies reported a definition of mental pain. 11.5% of studies did not show a measurement instrument of mental pain. The Cyberball (a social exclusion paradigm) was the most frequently used paradigm in experimental studies (62.7%). The cingulate cortex was the most frequently investigated biomarker category (15.3% of all candidate biomarkers), with fMRI as the most frequent investigation method (53.7% of all investigation methods).ConclusionsThe field of biological investigations on mental pain shows a marked heterogeneity of definitions, terms, hypotheses, experimental paradigms, and measurement instruments, with an over-representation of the construct of social pain and the Cyberball. These could compromise the comparison and combination of studies results in evidence synthesis and their translation into clinical practice.Disclosure of InterestNone Declared

2023

1. Abstract 5795: Leukemic stem cells confer ferroptosis resistance in aggressive blood cancer

   Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, and 1 more author

   Cancer Research, Apr 2023

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   Acute myeloid leukemia (AML) is an aggressive blood cancer with limited therapeutic options against leukemic stem cells (LSCs), resulting in poor clinical outcomes for decades. We have demonstrated the clinical importance of aberrant activation of RSPO3/β-catenin pathway in a subset of poor prognosis AML (Cancer Cell, 38:263-278, 2020) and its ability to sustain low levels of reactive oxygen species (ROS), a critical characteristic of human LSCs. This current study has extended our recent finding, and for the first time linked the pathway activation to ferroptosis resistance, a new drug resistance mechanism in cancer therapy. Our single-cell multiomics data in patient-derived xenograft mouse models of relapsed AML showed that the pathway activation in human LSCs led to upregulation of 43 differentially expressed genes associated with iron detoxification (e.g., FTH1) and ROS sensing/detoxification (e.g., PRDX1), two key features of ferroptosis resistance. Consistent with this observation, we found that AML patient specimens with favourable outcomes, which are independent of RSPO3 pathway, were sensitive to RSL3 treatment leading to increased cell death associated with elevated levels of intracellular ROS and iron. In contrast, AML patient specimens with poor clinical outcomes, which critically depend on RSPO3 pathway activation for survival and maintenance of myeloid undifferentiated state, revealed resistance to ferroptosis inducers (e.g., RSL3). Intriguingly, we found that anti-RSPO3 antibody, a clinical-grade drug that inhibits AML LSCs by blocking the interaction of RSPO3 with its receptor, sensitizes human LSCs to RSL3 treatment, leading to reduced cell viability. Overall, this study is the first to demonstrate the role of ferroptosis resistance in human LSCs and provides an opportunity to develop precision combination therapy by concurrently targeting self-renewal and ferroptosis resistance to improve therapeutic outcomes for patients with poor-risk AML.Citation Format: Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, Jenny Wang. Leukemic stem cells confer ferroptosis resistance in aggressive blood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5795.

2020

1. GADD45a Controls Self-Renewal in Acute Myeloid Leukemia Stem Cells

   Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, and 4 more authors

   Blood, Nov 2020

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   Acute myeloid leukemia (AML) is a heterogenous malignancy, where the persistence of chemo-resistant leukemia stem cells (LSCs) contributes to disease relapse. We have previously demonstrated the clinical significance of WNT/β-catenin signaling in driving AML LSCs (Science, 327:1650-1653, 2010; Cancer Cell, 38:1-16, 2020). In this study, we uncover that GADD45a (growth arrest and DNA-damage inducible protein) is an essential regulator of β-catenin signaling pathway and its loss promotes LSC function and leukemia progression.Transgenic knockout of Gadd45a led to a progressive increase in aberrant self-renewal and leukemogenesis in vivo. Gadd45a-/- leukemic cells developed a more aggressive leukemia with a shorter latency than Gadd45a+/+ cells in mice, indicating the involvement of Gadd45a loss in AML initiation and progression. Subsequent serial transplantation experiments showed that Gadd45a deletion enhanced LSC self-renewal in vivo. In agreement with our findings in murine LSCs, deletion of GADD45a by CRISPR/Cas9 in AML patient-derived xenograft (PDX) cells revealed increased engraftment and tumor burden in NSG mice. Consistent with our phenotypic observations, knockout of GADD45a increased βcatenin activity and key WNT/self-renewal target genes in human AML cells. In addition, our cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) data showed that GADD45a deletion in patient-derived LSCs was associated with cell metabolism, reactive oxygen species and tumor progression, as well as poor patient outcomes in AML. Further studies are being conducted to evaluate transcriptional mechanisms discovered by our single-cell sequencing.Taken together, this study is the first to demonstrate that GADD45a loss promotes LSC potential and consequently enhances tumor growth in murine and PDX models of AML, thus showcasing GADD45a as a promising therapeutic target in AML.References:Wang Y, Krivtsov AV, Sinha AU, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327:1650-1653.Salik B, Yi H, Hassan N, et al. Targeting RSPO-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia. Cancer Cell. 2020; 38:1-16.No relevant conflicts of interest to declare.