Biology subjects

Luck, C.

Publications and source records attributed to Luck, C..

8 recordsLinked to original sources

bioRxiv2025

First Generation Tools for the Modeling of Capicua (CIC) - Family Fusion Oncoprotein-Driven Cancers

Clinical divergence between patients harboring CIC-rearrangements is frequently observed. For example, the prototypical CIC::DUX4 fusion associates with soft tissue tumors while CIC::NUTM1 fusions typically localize to the CNS (brain/spinal cord). The basis for these differences is poorly understood due to a lack of molecular tools. To address this need, we generated patient-informed, synthetic coding sequences for CIC::NUTM1, CIC::LEUTX, and ATXN1::DUX4 and validated them in structure-function studies. We found that CIC::NUTM1 drives a transcriptional program distinct from that of CIC::DUX4 due to a C-terminal NUTM1 functional domain, CIC::LEUTX weakly activates CIC target genes through LEUTX transactivation sequences, and ATXN1::DUX4 upregulates CIC target genes via the ATXN1 AXH domain. Our findings indicate that the CIC fusion binding partner may alter overall fusion oncoprotein activity. Thus, these first generation synthetic tools provide an unprecedented resource to study CIC-family fusions beyond CIC::DUX4 and allow for the dissection of this rare subgroup of cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/653825v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1c1cf27org.highwire.dtl.DTLVardef@1073faforg.highwire.dtl.DTLVardef@e61455org.highwire.dtl.DTLVardef@140e952_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4. Significance StatementFusion oncogenes are neomorphic entities comprised of fractional coding sequences from two partner genes that have been inappropriately rearranged. The functional domains contributed by the partner genes shape the function of the resulting fusion. We use CIC::DUX4, a transcription factor fusion that drives an ultra-rare soft tissue sarcoma, to explore how preferential retention of a partner gene domain may influence the activity of the overall fusion. Our results indicate that the capicua C1 domain is retained in most CIC::DUX4 transcripts and is required for full activity of the CIC::DUX4 oncoprotein. We demonstrate that knowledge of where breakpoints occur and the resulting impact this has on the retention of functional domains can teach us about fusion behavior.

cancer biology↗

bioRxiv2023

Mapping chromatin state and transcriptional response in CIC-DUX4 undifferentiated round cell sarcoma

CIC-DUX4 is a rare and understudied transcription factor fusion oncoprotein. CIC-DUX4 co-opts native gene targets to drive a lethal form of human sarcoma. The molecular underpinnings that lead to oncogenic reprograming and CIC-DUX4 sarcomagenesis remain largely undefined. Through an integrative ChIP and RNA-Seq analysis using patient-derived CIC-DUX4 cells, we define CIC-DUX4 mediated chromatin states and function. We show that CIC-DUX4 primarily localizes to proximal and distal cis-regulatory elements where it associates with active histone marks. Our findings nominate key signaling pathways and molecular targets that enable CIC-DUX4 to mediate tumor cell survival. Collectively, our data demonstrate how the CIC-DUX4 fusion oncoprotein impacts chromatin state and transcriptional responses to drive an oncogenic program in undifferentiated sarcoma. SignificanceCIC-DUX4 sarcoma is a rare and lethal sarcoma that affects children, adolescent young adults, and adults. CIC-DUX4 sarcoma is associated with rapid metastatic dissemination and relative insensitivity to chemotherapy. There are no current standard-of-care therapies for CIC-DUX4 sarcoma leading to universally poor outcomes for patients. Through a deep mechanistic understanding of how the CIC-DUX4 fusion oncoprotein reprograms chromatin state and function, we aim to improve outcomes for CIC-DUX4 patients.

cancer biology↗

bioRxiv2023

Genome analysis of Legionella pneumophila ST901 an Italian endemic strain.

Legionella pneumophila typing, based on SBT analysis, has been allowing to identify sequence types (ST) responsible for many Legionnaires disease cases. ST901 has so far been identified only in a town of the northern Italy, where it caused numerous travel-associated Legionnaires disease cases over a 32-year period. In this study, ST901 were analyzed by whole genome sequencing in looking for both differences and similarities inside this ST and with other unrelated Legionella strains. To this aim core genome multi locus sequence type, single nucleotide polymorphisms and pangenome analyses were performed. ST901 resulted highly similar each other, characterized by I-C CRISPR-cas system, located on the chromosome and by a putative plasmid, highly similar to that found in Lp strain Lens, which contains I-F CRISPR-cas system. Accessory genomic islands, either already described or specifically found in ST901, were also shown. In conclusion ST901 has been quite preserved over the time. The co-occurrence of two phage resistance systems and genomic islands of virulence could have made the ST901 enough virulent to cause such a high number of cases. Summary blurbST901 appears as endemic of the Northern Italy, with virulence traits similar to those in Alcoy and Corby, and with two CRISPR-cas systems which probably preserved them in their environmental niche.

genomics↗

bioRxiv2023

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/524562v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17ea2a8org.highwire.dtl.DTLVardef@e8fcc7org.highwire.dtl.DTLVardef@2b9f8corg.highwire.dtl.DTLVardef@1f7b802_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Allosteric SHP2 Inhibition Increases Apoptotic Dependency on BCL2 and Synergizes with Venetoclax in FLT3- and KIT- Mutant AML

Mutations in receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppressed proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that SHP2 inhibition unveils an Achilles heel of AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in FLT3- or KIT-mutant AML cell lines, and in clinically relevant xenograft models. Our results provide new mechanistic rationale and preclinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML. SignificanceThere is an unmet need for effective therapies targeting the MAPK pathway to overcome resistance in RTK-driven AML. We report that pharmacologic co-inhibition of SHP2 and BCL2 has synergistic anti-leukemia activity in preclinical models of AML with FLT3 and KIT mutations and holds potential clinical utility.

cancer biology↗

bioRxiv2021

Transcriptional fidelity enhances cancer cell line selection in pediatric cancers

Multi-omic technologies have allowed for comprehensive profiling of patient-derived tumor samples and the cell lines that are intended to model them. Yet, our understanding of how cancer cell lines reflect native pediatric cancers in the age of molecular subclassification remains unclear and represents a clinical unmet need. Here we use Treehouse public data to provide an RNA-seq driven analysis of 799 cancer cell lines, focusing on how well they correlate to 1,655 pediatric tumor samples spanning 12 tumor types. For each tumor type we present a ranked list of the most representative cell lines based on correlation of their transcriptomic profiles to those of the tumor. We found that most (8/12) tumor types best correlated to a cell line of the closest matched disease type. We furthermore showed that inferred molecular subtype differences in medulloblastoma significantly impacted correlation between medulloblastoma tumor samples and cell lines. Our results are available as an interactive web application to help researchers select cancer cell lines that more faithfully recapitulate pediatric cancer.

cancer biology↗

bioRxiv2020

Atypical molecular basis for drug resistance to mitochondrial function inhibitors in Plasmodium falciparum

The continued emergence of drug-resistant Plasmodium falciparum parasites hinders global attempts to eradicate malaria, emphasizing the need to identify new antimalarial drugs. Attractive targets for chemotherapeutic intervention are the cytochrome (cyt) bc1 complex, which is an essential component of the mitochondrial electron transport chain (mtETC) necessary for ubiquinone recycling and mitochondrially localized dihydroorotate dehydrogenase (DHODH) critical for de novo pyrimidine synthesis. Despite the essentiality of this complex, resistance to a novel acridone class of compounds targeting cyt bc1 was readily attained, resulting in a parasite strain (SB1-A6) that was pan-resistant to both mtETC and DHODH inhibitors. Here we describe the molecular mechanism behind the resistance of the SB1-A6 parasite line which lacks the common cyt bc1 point mutations characteristic of resistance to mtETC inhibitors. Using Illumina whole-genome sequencing, we have identified both a copy number variation ([~]2x) and a single-nucleotide polymorphism (C276F) associated with pfdhodh in SB1-A6. We have characterized the role of both genetic lesions by mimicking the copy number variation via episomal expression of pfdhodh and introducing the identified SNP using CRISPR/Cas9 and assessed their contributions to drug resistance. Although both of these genetic polymorphisms have been previously identified as contributing to both DSM-1 (1) and atovaquone resistance (2, 3), SB1-A6 represents a unique genotype in which both alterations are present in a single line, suggesting that the combination contributes to the pan-resistant phenotype. This novel mechanism of resistance to mtETC inhibition has critical implications for the development of future drugs targeting the bc1 complex or de novo pyrimidine synthesis that could help guide future anti-malarial combination therapies and reduce the rapid development of drug resistance in the field.

microbiology↗