Biology subjects

Weigert, O.

Publications and source records attributed to Weigert, O..

5 recordsLinked to original sources

bioRxiv2026

MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer

MYC family members have been extensively studied as undruggable transcription factors regulating oncogenic signaling in highly aggressive tumors such as small cell lung cancer (SCLC), via promoter binding. Here, leveraging the previously described Myc-driven SCLC mouse model (RPM), we generated RPM-Miz1{Delta}POZ (RPMM) mice to uncover a Myc-dependent regulation of neuroendocrine (NE) differentiation, via enhancers. Our functional and genomic analyses reveal that Miz1 facilitates Myc binding to low-affinity E-boxes at distal chromosomal regions, thereby enabling Myc occupancy at sites with otherwise limited intrinsic affinity. We further show that SCLC patients and cellular models share an enrichment of low-affinity E-Box Myc binding motifs at enhancer regions that loop to genes of classic neuroendocrine differentiation. Integrated epigenetic and genomic analyses with AI-modeling implicate Myc/Miz1 binding at enhancers as the determinant for the expression of bona-fide neuroendocrine genes. In RPMM tumors, the suppression of neuroendocrine identity is paralleled by a redistribution of Myc protein towards promoter-proximal regions, hyper-activation of Myc transcriptional programs, apoptotic priming and enhanced sensitivity to etoposide. Together, these findings uncover Miz1/Myc-engaged enhancers as a central hub for neuroendocrine lineage programs and provide a mechanistic basis for a targeted inhibition of Miz1 to boost chemosensitivity in SCLC.

cancer biology↗

bioRxiv2023

ARID1A Mutations Protect Follicular Lymphoma from FAS-dependent Immune Surveillance by Reducing RUNX3/ETS1-Driven FAS-Expression

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18) (q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility ("openness"). However, the mechanism how ARID1A mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced stage disease at initial diagnosis and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including bispecific antibodies and CAR T cells.

cancer biology↗

bioRxiv2023

A single-cell multi-omic and spatial atlas of nodal B-cell lymphomas reveals B-cell maturation drives intratumor heterogeneity

Intratumor heterogeneity underpins cancer pathogenesis and evolution, although it is typically considered independent from the differentiation processes that drive physiological cell-type diversity. As cancer types and subtypes arise from different cell types, we investigated whether cellular differentiation influences intratumor heterogeneity. Nodal B-cell non-Hodgkin lymphomas are a diverse set of cancers originating from different stages of B-cell maturation. Through single-cell transcriptome and surface epitope profiling (CITE-Seq) of diffuse large B-cell, mantle cell, follicular, and marginal zone lymphomas in addition to reactive lymph nodes from 51 patients, we found multiple B-cell maturation states within tumors. Intratumor maturation states emerged from the same clone, revealing divergent differentiation from a shared cell of origin. Maturation state composition varied across subtypes and tumors, which encompassed mixed cell-of-origin diagnostic subtypes. Through highly multiplexed immunohistochemistry (CODEX) of samples from 19 of these patients, we found that intratumor maturation states inhabited distinct spatial niches, displaying cellular interactions and regulatory networks typical of their maturation states while harboring different genetic variants. By deconvoluting intratumor maturation states from a microarray dataset of 507 patients, we identified risk groups within diagnoses with striking differences in survival, including IgM memory-enriched germinal center B-cell (M = 1.9 vs >10 years, p = 0.00039) and activated B-cell (M = 2.4 vs 9.6 years, p = 0.016) diffuse large B-cell lymphoma, and dark zone-enriched follicular lymphoma (M = 8.6 vs 13 years; p = 0.0019). Our findings reveal cellular differentiation remains plastic in B-cell lymphomas, driving tumor variation, evolution, and response. Key PointsO_LICellular differentiation remains plastic in B-cell lymphomas, driving tumor variation, evolution, and response. C_LIO_LIIntratumor maturation states occupy unique immune niches, harbor distinct genetic variants, and are tied to different survival outcomes. C_LI

cancer biology↗

bioRxiv2022

Multimodal and spatially resolved profiling identifies distinct patterns of T-cell infiltration in nodal B-cell lymphoma entities

T-cell-engaging immunotherapies have improved the treatment of nodal B-cell lymphoma, but responses vary highly. Future improvements of such therapies require better understanding of the variety of lymphoma-infiltrating T-cells. We employed single-cell RNA and T-cell receptor sequencing alongside quantification of surface proteins, flow cytometry and multiplexed immunofluorescence on 101 lymph nodes from healthy controls, and patients with diffuse large B-cell, mantle cell, follicular, or marginal zone lymphoma. This multimodal resource revealed entity-specific quantitative and spatial aberrations of the T-cell microenvironment. Clonal PD1+ TCF7- but not PD1+ TCF7+ cytotoxic T-cells converged into terminally exhausted T-cells, the proportions of which were variable across entities and linked to inferior prognosis. In follicular and marginal zone lymphoma, we observed expansion of follicular helper and IKZF3+ regulatory T-cells, which were clonally related and inversely associated with tumor grading. Overall, we portray lymphoma-infiltrating T-cells with unprecedented comprehensiveness and decipher both beneficial and adverse dimensions of T-cell response.

cancer biology↗

bioRxiv2019

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors fully reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6 repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I dependent manner. Hence HDAC3-i represent a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas. STATEMENT OF SIGNIFICANCEWe have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP mutant cells in tandem with promoting anti-tumor immunity.

cancer biology↗