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PubMed2025

A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.

Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

Journal Article↗

PubMed2026

A distinct effector B cell population drives autoantibody production in SARS-CoV-2 infection.

Autoantibodies (autoAbs) are linked to mortality and Long COVID, yet their cellular origins remain unclear. We analyzed the INCOV cohort and identified 12 age- and sex-matched participants with varying autoAb abundance and integrated single-cell RNA-seq and ATAC-seq data from B cells, plasma proteomics, proteome-wide autoAb profiling, clinical data, and in vitro assays. AutoAb abundance inversely correlated with neutralizing IgG and declined as infection resolved, paralleling the contraction of atypical memory B cells (AtMs). In vitro, AtMs preferentially differentiated into autoAb-producing antibody-secreting cells upon TLR7/8 stimulation. CD11c+ AtMs (double-negative 2, DN2s) in autoAb-high individuals exhibited increased TLR7 signaling, oxidative stress, and isotype switching, regulated by transcription factors T-bet and XBP1. Integrated genetic and genomic analyses showed that DN2s had the strongest enrichment for autoimmune trait heritability and inferred regulatory effects of autoimmune risk variants among B cell subsets. These findings identify DN2s as key precursors of autoAb-producing cells during SARS-CoV-2 infection.

B cell↗

PubMed2026

TFAP2B and FOXC1 are associated with biologically and clinically distinct differentiation states in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) comprises biologically distinct subtypes, including luminal androgen receptor (LAR) tumors, but routine immunohistochemical markers incompletely capture lineage-associated differentiation states. We investigated TFAP2B, an AP-2 family transcription factor linked to epithelial differentiation, and FOXC1, a basal-like-associated transcription factor, as complementary markers of luminal and basal differentiation in TNBC. In a tissue microarray of 105 TNBCs, tumors were stratified as TFAP2B-dominant, FOXC1-dominant, or double-negative according to relative marker predominance and characterized using lineage, proliferation, molecular, immune, and chemotherapy-response parameters. TFAP2B-dominant tumors were associated with a coherent luminal phenotype, including apocrine/lobular enrichment, strong MUCL1 and AR expression, high CK18, low SOX10, reduced proliferation, frequent wild-type p53 patterns and retained RB1 expression, and low PD-L1 expression. FOXC1-dominant tumors showed contrasting basal-like features. These associations were independently supported at the transcriptional and genomic levels in the METABRIC TNBC cohort. FOXC1-dominant tumors also showed more frequent chemotherapy-induced downstaging than TFAP2B-dominant tumors. Together, we identify TFAP2B as a marker associated with luminal differentiation in TNBC and support combined TFAP2B/FOXC1 assessment as a practical framework for identifying clinically relevant TNBC differentiation states.

Humans↗

PubMed2026

ATP-Dependent Chromatin Remodelers in Prostate Cancer Progression and Therapeutic Resistance.

ATP-dependent chromatin remodelers (ACRs) have emerged as central determinants of prostate cancer (PCa) progression and therapy resistance. Organized into four mechanistically distinct families (SWI/SNF, ISWI, CHD, and INO80/SWR), ACRs govern nucleosome positioning genome-wide and thereby occupy a central position in the epigenomic regulatory landscape that dictates where and when transcription factors, including the androgen receptor (AR), can engage chromatin. This review discusses ACR dysregulation in PCa through both mutational and non-mutational mechanisms. These are illustrated by discussing how the functional consequences are highly context-dependent, varying with disease stage, prior treatment exposure, and tumor ancestry. Loss of the tumor suppressors RB1, TP53, and PTEN each generates specific ACR dependencies that are potentially therapeutically exploitable, including synthetic lethal relationships between PTEN deficiency and SWI/SNF ATPase activity. Across the spectrum of AR signaling states, from hormone-sensitive disease through therapy-resistant neuroendocrine and double-negative PCa subtypes, ACR complex composition and genomic targeting are continuously reprogrammed to enable and sustain lineage plasticity and endocrine therapy escape. Therapeutic strategies targeting SWI/SNF, ISWI, and INO80/SWR complexes are at varying stages of preclinical and clinical development and are attractive novel avenues to target therapy resistant PCa.

ATP dependent chromatin remodeling↗

PubMed2026

Multimodal computational framework resolves B cell maturation in autoimmunity and ageing.

Identification of the origin of pathogenic immune cells is crucial for therapeutic interventions and diagnosis but pseudotime methods struggle to trace immune cells accurately. Current trajectory inference methods for B cell development and response in health and disease either ignore or underutilize antigen receptor sequence information, limiting their ability to resolve developmental pathways, particularly for pathogenic populations. Widely used methods such as Monocle 3 reconstruct developmental paths from transcriptomic similarity alone, discarding the features from immune receptors. Dandelion has combined the immune receptor features with transcriptomics but it struggles to simulate the trajectory path of B cells. Here we present ClonoTrace, a computational framework that integrates BCR sequence features with transcriptomic trajectory inference through gated fusion of multimodal embeddings. In fetal B cell development and germinal centre development, ClonoTrace demonstrates closer concordance with the canonical reference ordering than Monocle 3 and Dandelion. Applied to systemic lupus erythematosus, ClonoTrace indicates a memory B cell extrafollicular maturation route alongside the naïve B cell route, accompanied by induction of ZEB2 with a concomitant decline of BACH2 along the trajectory, as a candidate alternative route to pathogenic double negative 2 B cells (DN2) in systemic lupus erythematosus (SLE) patients. In healthy ageing, ClonoTrace resolved three candidate age-related B cell maturation routes, from naïve, IgM+ memory and switched-memory B cells, each passing through a DN2-associated transcriptional state that is ordered before age-associated B cells along the inferred trajectory. ClonoTrace's fate probability algorithm indicated that IgM+ memory B cell to ABC transition as the leading candidate age-associated transition, which may be distinct from SLE DN2 maturation. ClonoTrace provides a generalizable framework for receptor-informed trajectory inference, describing candidate developmental routes of pathogenic B cell populations in autoimmunity and ageing.

Humans↗