Research Group Dr. Marco Seehawer
Histone modifier in tumor onset, progression, and therapy
Histone modifier in tumor onset, progression, and therapy
Histone-modifier are among the most mutated enzymes among all cancer types. One of their major roles is the alteration of histones as an important epigenetic regulation. However, they are also crucial for recruitment of and interaction with other epigenetic regulators, DNA damage repair complexes or pioneer transcription factors. This highlights their diverse functions in many cellular processes and their complexity as either tumor suppressor or tumor driver. Thus, therapeutical strategies in solid tumors targeting histone modifier directly or oncogenic pathways due to their loss of function are currently lacking.
Our lab aims to better understand these complex networks enhancing our knowledge about tumor initiating and driving events and developing combination treatment strategies. We use state-of-the-art sequencing approaches combined with in vitro and in vivo mouse models to validate our findings ensuring impactful research.
Tumor initiation and progression
We want to identify mechanisms how mutations in histone modifier account for early tumor development and progression focusing on intracellular mechanisms and regulation of cell communication pathways. Functional in vitro systems and sophisticated immunocompetent mouse models will be important techniques for this aim.
Targeted combination therapies
Using unbiased CRISPR screens and selected combination treatment strategies we aim to develop novel therapies focusing on histone modifier to target solid cancer and to overcome resistance to currently used standard therapies.
Epigenetic drivers of metalloproteinases and metastasis
Seehawer M, Polyak K.
Trends Cell Biol. 2025 Mar 14:S0962-8924(25)00044-3. doi: 10.1016/j.tcb.2025.02.010. Epub ahead of print. PMID: 40089451.
Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3
Seehawer M, Li Z, Nishida J, Foidart P, Reiter AH, Rojas-Jimenez E, Goyette MA, Yan P, Raval S, Munoz Gomez M, Cejas P, Long HW, Papanastasiou M, Polyak K.
Nat Cell Biol. 2024 Jul;26(7):1165-1175. doi: 10.1038/s41556-024-01446-3. Epub 2024 Jun 26. PMID: 38926506
Untangling the web of intratumour heterogeneity
Li Z, Seehawer M, Polyak K.
Nat Cell Biol. 2022 Aug;24(8):1192-1201. doi: 10.1038/s41556-022-00969-x. Epub 2022 Aug 8. PMID: 35941364.
Necroptosis microenvironment directs lineage commitment in liver cancer.
Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwälder M, Wang XW, Bischof O, Zender L.
Nature. 2018 Oct;562(7725):69-75. doi: 10.1038/s41586-018-0519-y. Epub 2018 Sep 12. Erratum in: Nature. 2018 Dec;564(7735):E9. doi: 10.1038/s41586-018-0723-9. PMID: 30209397; PMCID: PMC8111790.
More Publications
Whole-genome doubling drives immune evasion by silencing antigen presentation
Cancer Cell. 2026 Jul 13;44(7):1418-1436.e12. doi: 10.1016/j.ccell.2026.04.007. Epub 2026 May 7.
ABSTRACT
Whole-genome doubling (WGD) is a common yet poorly understood…
Identification of cycling regulatory T cell precursors as conductors of immune escape during breast carcinoma progression
Cancer Cell. 2026 Jun 8;44(6):1179-1200.e14. doi: 10.1016/j.ccell.2026.03.015. Epub 2026 Apr 16.
ABSTRACT
Immune escape during the ductal carcinoma in situ…
HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics during Evolution to Resistance to HER2-Targeted Therapies
Cancer Discov. 2026 Aug 3;16(8):1691-1710. doi: 10.1158/2159-8290.CD-25-1459.
ABSTRACT
Intratumor heterogeneity for human epidermal growth factor receptor 2 (HER2) in…
Regulation of the immune CD155-CD226-TIGIT axis by cyclin D-CDK4/6
Proc Natl Acad Sci U S A. 2026 Mar 24;123(12):e2522872123. doi: 10.1073/pnas.2522872123. Epub 2026 Mar 18.
ABSTRACT
Cyclin D-CDK4/6 is a component of mammalian…
Evaluation of targeted and immune combination therapies in a rat model of hormone receptor-positive breast cancer
Proc Natl Acad Sci U S A. 2026 Feb 10;123(6):e2501052123. doi: 10.1073/pnas.2501052123. Epub 2026 Feb 5.
ABSTRACT
Estrogen receptor (ER) positive breast cancer is the…
Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS
Cancer Cell. 2026 Feb 9;44(2):444-447. doi: 10.1016/j.ccell.2026.01.013. Epub 2026 Jan 31.
NO ABSTRACT
PMID:41621416 | DOI:10.1016/j.ccell.2026.01.013
KDM4C inhibition blocks tumor growth in basal breast cancer by promoting cathepsin L-mediated histone H3 cleavage
Nat Genet. 2025 Jun;57(6):1463-1477. doi: 10.1038/s41588-025-02197-z. Epub 2025 Jun 2.
ABSTRACT
Basal breast cancer is a subtype with a poor prognosis in need of more…
Epigenetic drivers of metalloproteinases and metastasis
Trends Cell Biol. 2025 Dec;35(12):1054-1067. doi: 10.1016/j.tcb.2025.02.010. Epub 2025 Mar 14.
ABSTRACT
Metalloproteinases (MPs) are crucial for development and…
ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer
Cell Rep. 2024 Dec 24;43(12):114991. doi: 10.1016/j.celrep.2024.114991. Epub 2024 Nov 20.
ABSTRACT
We previously described that the KDM5B histone H3 lysine 4 demethylase…
Midkine as a driver of age-related changes and increase in mammary tumorigenesis
Cancer Cell. 2024 Nov 11;42(11):1936-1954.e9. doi: 10.1016/j.ccell.2024.09.002. Epub 2024 Oct 3.
ABSTRACT
Aging is a pivotal risk factor for cancer, yet the underlying…
Cell Death and Survival Mechanisms in Cholangiocarcinogenesis
Am J Pathol. 2025 Mar;195(3):470-479. doi: 10.1016/j.ajpath.2024.06.014. Epub 2024 Aug 3.
ABSTRACT
Cholangiocarcinoma (CCA) and other liver cancer subtypes often develop…
Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3
Nat Cell Biol. 2024 Jul;26(7):1165-1175. doi: 10.1038/s41556-024-01446-3. Epub 2024 Jun 26.
ABSTRACT
KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases,…
Cancer-stromal cell interactions in breast cancer brain metastases induce glycocalyx-mediated resistance to HER2-targeting therapies
Proc Natl Acad Sci U S A. 2024 May 14;121(20):e2322688121. doi: 10.1073/pnas.2322688121. Epub 2024 May 6.
ABSTRACT
Brain metastatic breast cancer is particularly lethal…
Heterogeneity and transcriptional drivers of triple-negative breast cancer
Cell Rep. 2023 Dec 26;42(12):113564. doi: 10.1016/j.celrep.2023.113564. Epub 2023 Dec 14.
ABSTRACT
Triple-negative breast cancer (TNBC) is a heterogeneous disease with…
MYC determines lineage commitment in KRAS-driven primary liver cancer development
J Hepatol. 2023 Jul;79(1):141-149. doi: 10.1016/j.jhep.2023.02.039. Epub 2023 Mar 9.
ABSTRACT
BACKGROUND & AIMS: Primary liver cancer (PLC) comprises hepatocellular…
Breast cancer prevention by short-term inhibition of TGFβ signaling
Nat Commun. 2022 Dec 7;13(1):7558. doi: 10.1038/s41467-022-35043-5.
ABSTRACT
Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We…
JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States
Cancer Res. 2023 Jan 18;83(2):264-284. doi: 10.1158/0008-5472.CAN-22-0423.
ABSTRACT
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical…
Untangling the web of intratumour heterogeneity
Nat Cell Biol. 2022 Aug;24(8):1192-1201. doi: 10.1038/s41556-022-00969-x. Epub 2022 Aug 8.
ABSTRACT
Intratumour heterogeneity (ITH) is a hallmark of cancer that drives…
Platelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer
Nat Commun. 2021 Dec 1;12(1):7005. doi: 10.1038/s41467-021-27303-7.
ABSTRACT
Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all…
The immunological and metabolic landscape in primary and metastatic liver cancer
Nat Rev Cancer. 2021 Sep;21(9):541-557. doi: 10.1038/s41568-021-00383-9. Epub 2021 Jul 29.
ABSTRACT
The liver is the sixth most common site of primary cancer in humans,…
The Worst from Both Worlds: cHCC-ICC
Cancer Cell. 2019 Jun 10;35(6):823-824. doi: 10.1016/j.ccell.2019.05.008.
ABSTRACT
Prognosis of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma, a type…
Author Correction: Necroptosis microenvironment directs lineage commitment in liver cancer
Nature. 2018 Dec;564(7735):E9. doi: 10.1038/s41586-018-0723-9.
ABSTRACT
In this Article, the pCaMIN construct consisted of 'mouse MYC and mouse NrasG12V' instead of…
Necroptosis microenvironment directs lineage commitment in liver cancer
Nature. 2018 Oct;562(7725):69-75. doi: 10.1038/s41586-018-0519-y. Epub 2018 Sep 12.
ABSTRACT
Primary liver cancer represents a major health problem. It comprises…
microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-Associated Protein 1 to Suppress Hepatocarcinogenesis
Gastroenterology. 2018 Dec;155(6):1951-1966.e26. doi: 10.1053/j.gastro.2018.08.032. Epub 2018 Aug 27.
ABSTRACT
BACKGROUND & AIMS: We performed an integrated analysis to…
PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells
Cancer Cell. 2018 Jul 9;34(1):85-102.e9. doi: 10.1016/j.ccell.2018.06.007.
ABSTRACT
Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically,…
Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS
Cancer Cell. 2017 Jun 12;31(6):771-789.e6. doi: 10.1016/j.ccell.2017.05.006.
ABSTRACT
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer…
FAT1 expression and mutations in adult acute lymphoblastic leukemia
Blood Cancer J. 2014 Jun 27;4(6):e224. doi: 10.1038/bcj.2014.44.
NO ABSTRACT
PMID:24972153 | PMC:PMC4080215 | DOI:10.1038/bcj.2014.44