High-grade serous ovarian carcinoma (HGSOC), which accounts for approximately 75% of ovarian cancer cases, is associated with poor clinical outcome. Although most patients initially achieve a complete response to conventional chemotherapy, HGSOC almost invariably develops chemoresistance. There is therefore an urgent need to identify predictive biomarkers of treatment response. Here, through integrative analyses of molecular and clinical data from HGSOC patient cohorts, we identify syntabulin (SYBU), a microtubule-associated protein originally described as a regulator of mitochondrial transport along neuronal microtubules, as a critical determinant of chemosensitivity in HGSOC. Low SYBU expression in tumors correlates with higher tumor grade and increased aggressiveness, yet paradoxically with enhanced sensitivity to chemotherapy. SYBU-deficient cancer cells display impaired oxidative phosphorylation and a metabolic shift toward glycolysis characteristic of the Warburg effect, together with mitotic defects such as chromosome lagging that promote aneuploidy. Mechanistically, syntabulin forms a complex with the mitochondrial outer membrane porin VDAC1 and the inner membrane protein MIC60, a major regulator of mitochondrial cristae organization. Functionally, the syntabulin-MIC60 axis controls cristae architecture and mitotic fidelity, thereby connecting mitochondrial metabolism to cell division. These findings highlight new therapeutic vulnerabilities to overcome chemoresistance in ovarian cancer. ### Competing Interest Statement The authors have declared no competing interest. Fondation ARC pour la Recherche sur le Cancer, https://ror.org/0489qz649, Post-doctoral fellowship for H.M, Subvention 2017-2019 for C.N, Passerelle Grant for E.P, MetaboPlast-ARCPJA2022060005283 for C.B Fondation de France, 00119147/WB-2021-35655 for H.M La Ligue Contre le Cancer, https://ror.org/00rkrv905, PhD Fellowship for M.M, Ligue Contre le Cancer 94/Val de Marne subvention for C.N Entreprises contre le Cancer Paris GEFLUC, metabolic analysis for G.G and F.M.-G, GEFLUC SYBU subvention 2024 for C.N, GEFLUC SYBU subvention 2025 for C.N, GEFLUC subvention 2023-2024 for C.B Institut National du Cancer (INCa), INCa 2017-1-PL BIO-08 and 2021 - 167/ INCA_16344 for C.B Société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent (SFCE), ECS 20, PHC PESSOA, N°49163TL for C.B Eva pour la vie-Grandir Sans Cancer, EPLVGSD2025-Brenner for C.B Fondation Rothschild, Paris, France, Subvention Ovarian cancer chemoresistance 2023-2025 for C.N University Paris Saclay, Emergence LERMIT MitoMicro 2021 for C.N, GS-LSH project MIMIMI 2023-2025 for C.N Agence Nationale de la Recherche, MetaboInov, ANR-24-CE14-6636-01 for C.B ODYSSÉA association, 2020-2025 for C.N Association PROLIFIC, SYBU project 2019-2025 for C.N AIRC, Italy, IG-23670 for P.P Progetti di Rilevante Interesse Nazionale, PRIN20227Z2XRB to M.B, 2020RRJP5L, 202259LHXM, P2022WY85K_001, PNRR-CN00000041 to P.P

Gene set enrichment analysis (GSEA) comparing SPI1 WT (n = 29) versus QE (n = 3) WM RNAseq samples (MSigDB database) (H, hallmark gene sets)

Gene set enrichment analysis (GSEA) from RNA-seq obtained upon SPI1 WT (n = 3) and QE (n = 3) expression in OCI-Ly10 cells (Lymphochip database)

The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.

We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.

PDF file - 98KB, Biological and clinical features of the 168 CLL patients according to EGR2, NFKBIE and BRAF mutations.

PDF file - 116KB, Association between acquired mutations (P values of Fisher's exact test for independence) among the 168 patients cohort.

PDF file - 272K, Supplemental figure S1: Correlation analysis between proliferation marker MIK67 and the spliceosome-related genes Supplemental figure S2: Expression of the indicated spliceosomal components in SNRPE or SNRPD1-depleted cells. Supplemental figure S3: Effect of siRNA-mediated depletion of SNRPE or SNRPD1 on cell viability in additional breast, melanoma and lung tumoral cell lines Supplemental figure S4: Correlation analysis between the proliferation rate of all tested cell lines tested and their sensitivity to SNRPE or SNRPD1 depletion Supplemental figure S5: Apoptosis detection in SKBr-3 cell line following SNRPD1 depletion Supplemental figure S6: Genes whose initial exon expression is modulated by SNRPE. Supplemental figure S7: Expression of GUSB and RPLPO control genes in SNRPE-depleted cells treated or not with cycloheximide

Supplementary Figure, Table and Movie Legends from miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death

Supplementary Movie 1 from miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death

XLS file - 336KB, Biological and clinical features of the 24 patients included in the whole-exome study.

Supplementary Figures 1-3 from Microarray-Based Identification of Tenascin C and Tenascin XB, Genes Possibly Involved in Tumorigenesis Associated with Neurofibromatosis Type 1

PDF file - 490K, Supplementary Table S1. Systematic comparison of the effects of CDDP and PARP inhibitors on cancer cell lines used in this study. Supplementary Figure S1. Generation and characterization of CDDP-resistant human NSCLC cell clones. Supplementary Figure S2. Effects of CDDP and PARP inhibitors on the intracellular levels of poly(ADPribosyl) ated proteins in WT and CDDP-resistant NSCLC cells. Supplementary Figure S3. DNA damage as induced by PARP inhibitors is not a consequence of apoptotic caspase activation. Supplementary Figure S4. Markers of homologous recombination (HR) in CDDP-sensitive and CDDP-resistant A549 cells responding to PARP inhibitors. Supplementary Figure S5. DNA repair activity of A549 cell extracts towards dAT- and THFT-containing substrates. Supplementary Figure S6. DNA glycosylase activity of A549 cell extracts towards HxT- and UG-containing substrates. Supplementary Figure S7. DNA repair activity of A549 cell extracts towards 5-OHCT-and 8oxoGC-containing substrates. Supplementary Figure S8. Expression levels and functional activity of XRCC1 and POL in CDDP-sensitive and CDDP-resistant cancer cells that overexpress PARP1 and contain high levels of poly(ADP-ribosyl)ated proteins.

PDF file - 211KB, Biological and clinical features of the 24 patients included in the whole-exome study.

PDF file - 136KB, Representative flow chart of the sorting procedure.

PDF file, 67K, Hierarchical clustering of 82 tumors based on Chromosomal abnormalities analyzed by 244k aCGH.

Abstract Non–small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor–induced apoptosis. Cancer Res; 73(7); 2271–80. ©2013 AACR.

PDF file - 170KB, Early mutations affect genes mutated in various human cancers (addition to the main text).