---
title: "MYC–MIZ1 Enhancer Complexes Regulate Neuroendocrine Identity in Small Cell Lung Cancer"
id: "biorxiv-7-myc-miz1-complexes-at-enhancers-tune-neuroendocrine-identity-of-small-cell-lung"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-7-myc-miz1-complexes-at-enhancers-tune-neuroendocrine-identity-of-small-cell-lung"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.19.745709v1?rss=1"
published_at: "2026-08-20T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# MYC–MIZ1 Enhancer Complexes Regulate Neuroendocrine Identity in Small Cell Lung Cancer
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-7-myc-miz1-complexes-at-enhancers-tune-neuroendocrine-identity-of-small-cell-lung
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.19.745709v1?rss=1)
- **Published At:** 2026-08-20T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study uses a previously described **Myc**-driven SCLC mouse model (RPM) and generates RPM-Miz1 ΔPOZ (RPMM) mice to probe Myc-dependent control of neuroendocrine (NE) differentiation via distal regulatory elements. - Functional and genomic assays show that **Miz1** facilitates **Myc** binding to low-affinity E-box motifs located in distal enhancer regions, enabling Myc occupancy at sites with otherwise limited intrinsic affinity. - Integrated epigenetic and genomic analyses, combined with AI modeling, indicate that **Myc/Miz1 binding at enhancers** determines expression of bona fide neuroendocrine genes. - Analyses of SCLC patient samples and cellular models reveal an enrichment of low-affinity E-box **Myc** binding motifs at enhancer regions that physically loop to classical NE differentiation genes. - In RPMM tumors (Miz1 POZ domain deletion), loss of enhancer-engaged Myc/Miz1 is associated with suppression of **neuroendocrine identity**, a redistribution of Myc protein toward promoter-proximal regions, and hyperactivation of Myc transcriptional programs. - RPMM tumors display features of apoptotic priming and show increased sensitivity to the chemotherapeutic agent etoposide relative to control tumors. - The findings position **Miz1/Myc-engaged enhancers** as a central regulatory hub for NE lineage programs in SCLC and provide a mechanistic rationale for targeting **Miz1** to augment chemosensitivity. - The preprint reports authorship, funding sources, posted date (August 20, 2026), and declared competing interests; methodological and numerical details were not fully reported in the abstract-level source provided.
## Clinical Analysis & Structured Key Points
MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer | bioRxiv Skip to main content New Results MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer Lisa M. Froehlich , Hannah L. Tumbrink , Bikash Adhikari , Margarita Rempe , Jenny Ostendorp , Paula Zickler , Michaela Hoehne-Wiechmann , Alena Heimsoeth , Yichun Tang , Stefanie Lennartz , Ayla Schwaebe , Lisa Werr , Matthias Fischer , Alexander Quaas , Holger Gruell , Katia Garbert , Daniela Morgenthaler , Marian Touet , Johannes A. Hildebrand , Oliver Weigert , Filippo Beleggia , Dimitrios Papadopoulos , Elmar Wolf , Johannes Braegelmann , Julia Frede , Robert Haensel-Hertsch , Martin L. Sos doi: https://doi.org/10.64898/2026.08.19.745709 Lisa M. Froehlich 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hannah L. Tumbrink 2 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bikash Adhikari 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Margarita Rempe 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jenny Ostendorp 3 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany / Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Paula Zickler 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michaela Hoehne-Wiechmann 2 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alena Heimsoeth 2 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yichun Tang 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stefanie Lennartz 2 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ayla Schwaebe 2 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lisa Werr 4 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany / Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany / Department of Experimental Pediatr; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthias Fischer 5 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany / Department of Experimental Pediatric Oncology, University Childrens Hospital of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexander Quaas 6 University of Cologne, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Holger Gruell 7 University of Cologne, Department of Radiology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Katia Garbert 8 Deans Office, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniela Morgenthaler 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marian Touet 9 Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany / Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Johannes A. Hildebrand 10 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), LMU Universi; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Oliver Weigert 10 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), LMU Universi; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Filippo Beleggia 11 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany / Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Ge; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dimitrios Papadopoulos 12 Mildred Scheel Nachwuchszentrum, University of Wuerzburg, Am Hubland, Wuerzburg, Germany / Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Wuerzburg, Am Hubland, Wuerzburg, German; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elmar Wolf 13 Institute of Biochemistry, University of Kiel, Kiel, Germany; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Johannes Braegelmann 14 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany / Mildred Scheel School of Oncology Aachen Bonn Cologne Duesseldorf (MSSO ABCD), Faculty of Medicine and University Hospital; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julia Frede 15 Technical University of Munich, School of Medicine and Health, Institute of Laboratory Medicine, TUM University Hospital; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert Haensel-Hertsch 16 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany / Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany / Cologne Excellence Cluster on Cell Find this author on Google Scholar Find this author on PubMed Search for this author on this site Martin L. Sos 1 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany / Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany / Department of Translational Oncology, German Cancer Research Center (DKFZ), LMU; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: martin.sos{at}dkfz-heidelberg.de Abstract Info/History Metrics Supplementary material Preview PDF Abstract 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 ΔPOZ (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. Competing Interest Statement J.B. has received research funding from Bayer AG outside the reported work. M.L.S. is a founder of PearlRiver Bio, acquired by Centessa, a shareholder of Centessa and received funding from PearlRiver Bio. R.H.-H. is a consultant to Active Motif. Funder Information Declared Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64 , 413326622 , SO 1155/5 , GRK2338 (P13) , 493872418 , 325931972 , BR 6949/2-1 Fritz Thyssen Foundation, https://ror.org/00f3sc705 , 10.19.2.025MN Bayerisches Zentrum für Krebsforschung , BGF/25/05/LMU/Sos , BGF/24/08/LMU/Sos Ministry of Culture and Science of the State of North Rhine-Westphalia , NW21-062B German Cancer Aid, https://ror.org/01wxdd722 , 70113307 , 70116929 , 70116707 , DEFEAT-PDAC-70117118 Bundesministerium für Bildung und Forschung , 01ZX1303 , 01ZX1603 , 01ZX1307 , 01ZX1607 Wilhelm Sander Stiftung , 2022.093.1 European Research Council , 101164889 , 101087045 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Back to top Previous Next Posted August 20, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer Lisa M. Froehlich , Hannah L. Tumbrink , Bikash Adhikari , Margarita Rempe , Jenny Ostendorp , Paula Zickler , Michaela Hoehne-Wiechmann , Alena Heimsoeth , Yichun Tang , Stefanie Lennartz , Ayla Schwaebe , Lisa Werr , Matthias Fischer , Alexander Quaas , Holger Gruell , Katia Garbert , Daniela Morgenthaler , Marian Touet , Johannes A. Hildebrand , Oliver Weigert , Filippo Beleggia , Dimitrios Papadopoulos , Elmar Wolf , Johannes Braegelmann , Julia Frede , Robert Haensel-Hertsch , Martin L. Sos bioRxiv 2026.08.19.745709; doi: https://doi.org/10.64898/2026.08.19.745709 Share This Article: Copy Citation Tools MYC-MIZ1 Complexes at Enhancers Tune Neuroendocrine Identity of Small Cell Lung Cancer Lisa M. Froehlich , Hannah L. Tumbrink , Bikash Adhikari , Margarita Rempe , Jenny Ostendorp , Paula Zickler , Michaela Hoehne-Wiechmann , Alena Heimsoeth , Yichun Tang , Stefanie Lennartz , Ayla Schwaebe , Lisa Werr , Matthias Fischer , Alexander Quaas , Holger Gruell , Katia Garbert , Daniela Morgenthaler , Marian Touet , Johannes A. Hildebrand , Oliver Weigert , Filippo Beleggia , Dimitrios Papadopoulos , Elmar Wolf , Johannes Braegelmann , Julia Frede , Robert Haensel-Hertsch , Martin L. 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