Low-lying octupole isovector excitation in Nd-144

International audienceThe nature of low-lying 3− levels in Nd144 was investigated in the Nd143(n,γγ) cold neutron-capture reaction. The combination of the high neutron flux from the research reactor at the Institut Laue-Langevin and the high γ-ray detection efficiency of the EXILL setup allowed the recording of γγ coincidences. From the coincidence data precise branching ratios were extracted. Furthermore, the octagonal symmetry of the setup allowed angular-distribution measurements to determine multipole-mixing ratios. Additionally, in a second measurement the ultra-high resolution spectrometer GAMS6 was employed to conduct lifetime measurements using the gamma-ray induced Doppler-shift technique (GRID). The confirmed strong M1 component in the 33−→31− decay strongly supports the assignment of the 33− level at 2779keV as low-lying isovector octupole excitation. Microscopic calculations within the quasiparticle phonon model confirm an isovector component in the wave function of the 33− level, firmly establishing this fundamental mode of nuclear excitation in near-spherical nuclei

Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors

CAMTA1, a 1p36 tumor suppressor candidate, inhibits growth and activates differentiation programs in neuroblastoma cells

A distal portion of human chromosome 1p is often deleted in neuroblastomas and other cancers and it is generally assumed that this region harbors one or more tumor suppressor genes. In neuroblastoma, a 261 kb region at 1p36.3 that encompasses the smallest region of consistent deletion pinpoints the locus for calmodulin binding transcription activator 1 (CAMTA1). Low CAMTA1 expression is an independent predictor of poor outcome in multivariate survival analysis, but its potential functionality in neuroblastoma has not been explored. In this study, we used inducible cell models to analyze the impact of CAMTA1 on neuroblastoma biology. In neuroblastoma cells that expressed little endogenous CAMTA1, its ectopic expression slowed cell proliferation, increasing the relative proportion of cells in G(1)/G(0) phases of the cell cycle, inhibited anchorage-independent colony formation, and suppressed the growth of tumor xenografts. CAMTA1 also induced neurite-like processes and markers of neuronal differentiation in neuroblastoma cells. Further, retinoic acid and other differentiation- inducing stimuli upregulated CAMTA1 expression in neuroblastoma cells. Transciptome analysis revealed 683 genes regulated on CAMTA1 induction and gene ontology analysis identified genes consistent with CAMTA1-induced phenotypes, with a significant enrichment for genes involved in neuronal function and differentiation. Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma

In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.

Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models

A mechanistic classification of clinical phenotypes in neuroblastoma

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients

Lifetime measurements in Ti 52,54 to study shell evolution toward N=32

AGATA CollaborationLifetimes of the excited states in the neutron-rich Ti52,54 nuclei, produced in a multinucleon-transfer reaction, were measured by employing the Cologne plunger device and the recoil-distance Doppler-shift method. The experiment was performed at the Grand Accélérateur National d'Ions Lourds facility by using the Advanced Gamma Tracking Array for the γ-ray detection, coupled to the large-acceptance variable mode spectrometer for an event-by-event particle identification. A comparison between the transition probabilities obtained from the measured lifetimes of the 21+ to 81+ yrast states in Ti52,54 and that from the shell-model calculations based on the well-established GXPF1A, GXPF1B, and KB3G fp shell interactions support the N=32 subshell closure. The B(E2) values for Ti52 determined in this work are in disagreement with the known data, but are consistent with the predictions of the shell-model calculations and reduce the previously observed pronounced staggering across the even-even titanium isotopes