Biology subjects

Frede, J.

Publications and source records attributed to Frede, J..

3 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↗

bioRxiv2026

Altered immune and treatment response gene expression signatures among poverty-exposed children with B-ALL

Children diagnosed with cancer typically receive standardized treatment regimens. Despite highly protocolized care, children living in poverty experience a greater risk of cancer relapse and higher mortality compared to their more affluent peers.1,2 Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, and children with ALL exposed to poverty are more likely to experience early relapse.3 Using single-cell RNA sequencing to analyze leukemic blasts and their microenvironment at diagnosis we found that poverty-exposed patients with standard-risk B-ALL exhibit transcriptional signatures of steroid resistance at time of diagnosis. Additionally, we observe increased expression of inflammatory signatures in myeloid cells and reduced effector signatures in CD8+ T-cells in children with B-ALL living in poverty. Further investigation of the mechanisms underlying these associations may identify opportunities for risk-adapted therapeutic strategies to improve disease outcomes in pediatric ALL.

cancer biology↗

bioRxiv2024

Differential KEAP1/NRF2 mediated signaling widens the therapeutic window of redox-targeting drugs in SCLC therapy

Small cell lung cancer (SCLC) patients frequently experience a remarkable response to first-line therapy. Follow up maintenance treatments aim to control residual tumor cells, but generally fail due to cross-resistance, inefficient targeting of tumor vulnerabilities, or dose-limiting toxicity, resulting in relapse and disease progression. Here, we show that SCLC cells, similar to their cells of origin, pulmonary neuroendocrine cells (PNECs), exhibit low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a novel thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, regardless of their molecular subtype or resistance to first-line therapy. Importantly, unlike non-cancerous cells, SCLC cells cannot adapt to drug-induced ROS stress due to the suppression of ROS defense mechanisms by multiple layers of epigenetic and transcriptional regulation. By exploiting this difference in oxidative stress management, we safely increased the therapeutic dose of TXNRD1 inhibitors in vivo by pharmacological activation of the NRF2 stress response pathway. This resulted in improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors for maintenance therapy in SCLC. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/621846v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@2a7336org.highwire.dtl.DTLVardef@f21de9org.highwire.dtl.DTLVardef@189d062org.highwire.dtl.DTLVardef@cff38b_HPS_FORMAT_FIGEXP M_FIG C_FIG Pharmacological induction of NRF2 leads to differential cyto-protection against TXNRD1 inhibitors in normal tissue but not in SCLC tumor cells. This results in a reduction of adverse effects, allowing to increase the therapeutic dose.

cancer biology↗