Biology subjects

Riggi, N.

Publications and source records attributed to Riggi, N..

5 recordsLinked to original sources

bioRxiv2026

ALK variants Differentially Modulate Neuroblastoma Tumor Behavior and Transcriptome in a Cellular Context-Dependent Manner

High-risk neuroblastoma remains a major clinical challenge despite intensive multimodal treatment. Alterations in the anaplastic lymphoma kinase (ALK) gene are frequent in NB and correlate with poor outcome. ALK-F1174L and ALK-R1275Q are the most prevalent activating mutations, but their specific effects on tumor behavior remain unclear. Here, we compared the impacts of ALK-wild-type (wt), ALK-F1174L and ALK-R1275Q in several NB xenograft models. In the SK-N-Be2c model, ALK-F1174L mediated numerous transcriptomic alterations without affecting tumor behavior. In GIMEN cells, only ALK-F1174L and ALK-R1275Q conferred tumorigenicity with distinct growth kinetics and transcriptional programs. In the mesenchymal SH-EP model, ALK variants induced distinct phenotypes, with ALK-wt and ALK-F1174L promoting partial transition toward neuroblastic identity. All ALK variants induced lung metastases, but with allele-specific dissemination patterns. Transcriptomic profiling of SH-EP tumors and corresponding metastases revealed partly opposing pathway regulation between ALK-F1174L and ALK-R1275Q. Overall, ALK variants differentially modulate NB behavior in a context-dependent manner.

cancer biology↗

bioRxiv2026

scLANTERN: High-Throughput Retrospective Lineage Tracing via Full-Length Single-Cell Transcriptomics and Expressed Repeat Variation

Understanding the lineage relationships among individual cells is a key pursuit of modern biology, essential for unraveling the complexities of developmental processes and the adaptive mechanisms of disease progression, particularly in oncology. Retrospective single-cell clonal tracing has emerged as a transformative approach, offering a unique window into the evolutionary trajectories of cancer within clinical samples. While short-read single-cell transcriptomics (scRNA-seq) has revolutionized our ability to map cell states across human tumor atlases, it remains fundamentally limited in its capacity to link these states with high-resolution genomic alterations and the evolutionary trajectories inferred from these natural variants. Integrating somatic mutation discovery with transcriptomic profiles at single-cell resolution often requires separate, costly, and low-throughput genomic assays. Furthermore, existing methods frequently rely on exogenous genetic labeling or are restricted to short-read sequencing, which typically fails to resolve complex genomic rearrangements, large indels, or variations within highly repetitive regions,such as short tandem repeats (STRs), that could serve as potent endogenous clonal markers.

evolutionary biology↗

bioRxiv2023

KDM6 demethylases mediate EWSR1-FLI1-driven oncogenic transformation in Ewing Sarcoma

Ewing Sarcoma (EwS) is an aggressive bone and soft tissue tumor driven by the fusion oncoprotein EWSR1-FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neo-enhancers in a permissive cellular context. Inhibition of the oncogene remains challenging and current efforts instead seek to exploit emergent epigenetic treatments targeting EWSR1-FLI1 cofactors. Here, stemming from the genome-wide redistribution of H3K27me3 upon expression of EWSR1-FLI1 in pediatric hMSC, we unravel the contribution of the H3K27me3 demethylases KDM6A and KDM6B in transcriptional activation at EWSR1-FLI1 enhancers. We found that KDM6A has a demethylase-independent role in recruiting the SWI/SNF member BRG1 at EWSR1-FLI1-primed enhancers containing single GGAA motif, which is critical for EwS tumor growth. Conversely, KDM6B demethylates H3K27me3 at EWSR1-FLI1-active enhancers containing multimeric GGAA repeats and its deletion synergizes with EZH2 inhibitors. Our results highlight KDM6 demethylases as EWSR1-FLI1 cofactors with potential for future targeted therapies.

cancer biology↗

bioRxiv2021

TWIST1 expression is associated with high-risk Neuroblastoma and promotes Primary and Metastatic Tumor Growth

The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings suggest TWIST1 as novel therapeutic target in NB.

cancer biology↗

bioRxiv2019

Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma

Synovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels. To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies.

cancer biology↗