Stem Cells and Cancer

Hematopoietic stem cells (HSC) maintain lifelong blood cell production based on their capacity for extensive self-renewal and multipotency. Moreover, HSCs are critical to regenerate the blood system after stress conditions such as inflammation, blood loss or toxic insults such as chemotherapy.

→ Signature Discovery of the Trumpp team: Identified, defined and characterized “dormant” HSCs as a protected reserve, which can be activated by bone marrow stress and proposed a “Waddington-like” continuous hematopoiesis model to generate progenitors and lineage primed blood cells downstream of HSCs.

• First characterization of dormant HSCs: Dormancy protects their genomic integrity and make them resistant to chemotherapy, but can be activated by inflammatory signals such as interferons (Wilson et al., Cell 2008, Essers et al., Nature 2009, Walter et al., Nature 2015)

• Identified regulators of HSC dormancy and function including MYC, retinoic acid, Netrin-1, and alternative polyadenylation (Wilson et al., Genes & Development 2004, Scognamiglio et al., Cell 2016, Cabezas-Wallscheid et al., Cell 2017, Bahr et al., Nature 2018, Sommerkamp et al., Cell Stem Cell 2020).

• Together with Lars Steinmetz team (EMBL), proposed the continuous “Waddington-like” hematopoiesis model – overturning the classical tree model for hematopoiesis (Velten et al., Nature Cell Biology 2017).

• Revealed HSCs can function as antigen-presenting cells (Hernàndez-Malmierca et al., Cell Stem Cell 2022).

• Established the MPP1-6 nomenclature for progenitors immediately downstream of HSCs (Cabezas-Wallscheid et al., Cell Stem Cell 2014, Sommerkamp et al., Blood 2021).

• Identified a novel highly dormant HSC with lymphoid primed characteristics that becomes important during ageing (Lin et al., in revision 2026).

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy in which disease initiation, therapy resistance, and relapse are driven by leukemic stem cells (LSCs). The LSC compartment is highly heterogeneous, a key determinant of variable therapeutic responses. This heterogeneity arises from both genetic and non-genetic factors, including somatic mutations, cell of origin, transcriptional and epigenetic states, and pronounced phenotypic plasticity. LSCs that survive therapy fuel clonal evolution, disease persistence, and relapse.

Beyond intensive and often highly toxic standard combination chemotherapies, treatment with the BCL-2 inhibitor venetoclax in combination with hypomethylating agents (e.g., 5-azacytidine) is currently transforming AML therapy and is expected to become a standard first-line treatment. We recently developed the MAC score, a personalized predictive biomarker system that enables stratification of AML patients according to their likelihood of response or resistance to venetoclax-based therapies.

→ Signature Discovery of the Trumpp team: Characterized the genetic and non-genetic heterogeneity of AML stem cells in patients at the molecular and cellular level. Developed MAC-Scoring, the first clinically useful biomarker to predict Venetoclax response in patients with high accuracy.

• Identified BCAT1, controlling branched-chain amino acid catabolism, as a metabolic driver mimicking IDH/TET2 mutations, and which is upregulated in patients in response to IDH-inhibitor mediating resistance (Raffel et al., Nature 2017, Raffel et al., Blood 2020).

• Together with Claudia Lengerke team (University Hospital Tübingen), uncovered LSC immune evasion and showed PARP1 inhibition restores NK surveillance (Paczulla et al., Nature 2019) – now entering clinical trials.

• Tracked clonal evolution in AMLs with complex karyotype (CK-AML) with single-cell multi-omics profiling – uncovering relapse and therapy resistance mechanisms employed by LSCs (Leppä et al., Nature Genetics 2024). 

• Invented MAC-Scoring as a reliable predictive clinical biomarker for Venetoclax (BCL-2 inhibitor) response: a rapid (6h), affordable, and clinically applicable assay that precisely predicts individual AML patient response to VEN/HMA therapy by flow cytometric measuring expression of three BCL-2 family members in LSCs (Waclawiczek et al., Cancer Discovery 2023). MAC-Scoring is established in various Hematology-Oncology clinics in Germany, New York, and Mexico, directly guiding treatment decisions.

Breast cancer (BC) treatment and prognosis have been greatly improved in recent years. Nevertheless, metastatic BC (MBC) remains incurable. BC cells spread mainly to the lungs, liver, bones, lymph nodes and brain. The source of metastases is circulating tumor cells (CTCs) with metastasis-initiating stem cell potential. CTCs disseminated to the blood by the primary tumor drive metastasis, the leading cause of death in individuals with cancer including BC. 

→ Signature Discovery of the Trumpp team: First to isolate metastasis stem cells directly from patient blood and established a platform to expand these cells as organoids and characterize them at the molecular and functional level associated to clinical precision oncology programs.

• First experimental proof that CTCs induce metastasis and identified CD44⁺MET⁺CD47⁺ CTCs as drivers of bone and lung metastases (Baccelli et al., Nature Biotechnology 2013)

• Created a CTC-derived organoid platform to expand CTCs from patient blood: revealing NRG1-HER2/3 and plasticity on FGFR1 as therapy escape pathways (Würth et al., Nature Cancer 2025; Schwerd-Kleine et al., Int J of Cancer 2025).

Pancreatic ductal carcinoma (PDAC) starts in the cells lining the pancreatic ducts. It is often diagnosed late and is difficult to treat, with overall 5-year survival rates around 10%. PDAC is associated to a desmoplastic stroma and hypertrophic nerves. Novel treatment schemes need to be developed to target this dismal disease. 

→ Signature Discovery of the Trumpp team: Identified therapy resistance pathways and revealed the cross-talk between peripheral nerves and pancreatic cancer as a novel therapeutic target revealing new treatment concepts for PDAC.

• Identified CYP3A5 as a resistance driver, now targeted with novel inhibitors (Noll et al., Nature Medicine 2016; Kuhlmann et al. Pancreas 2017).

• Defined an inflammatory PDAC subtype driven by retroelement activation regulated by differential DNA methylation of the pancreatic cancer genome (Espinet et al., Cancer Discovery 2021).

• The peripheral nervous system (PNS) orchestrates organ function in health and disease. Most cancers, including PDAC are infiltrated by PNS neurons. However, neuronal cell bodies reside in various PNS ganglia, far from the tumour mass. Thus, cancer-innervating or healthy-organ-innervating neurons are lacking in current tissue-sequencing datasets. To address this, the Trump team developed the Trace-n-Seq method, enabling for the first time to obtain single-cell transcriptomics data of innervating neurons of healthy pancreas and PDAC. This revealed a striking reprogramming of innervating neurons and nerves by the PDAC tumor to promote its own growth and metastasis (Thiel, Renders et al., Nature 2025).

• Showed that neuronal blockade (denervation) synergizes with taxane-mediated chemo- and immunotherapy providing the basis for new clinical trials (Thiel, Renders et al., Nature 2025)