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Biomedical subjects

Thorsten Stiewe

Publications and source records attributed to Thorsten Stiewe.

3 recordsLinked to original sources
PubMed2026

A pro-inflammatory metastasis-associated macrophage subset induces tumor-promoting mesothelial cell conversion in ovarian cancer via IL-1α secretion.

Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment, yet the functional specialization of TAM subsets in metastatic progression remains incompletely defined. Here, we characterized distinct TAM populations contributing to tumor-promoting mesothelial cell conversion in high-grade ovarian carcinoma using single-cell RNA sequencing of patient-derived macrophages from ascites (ascTAMs) and omental metastases (omTAMs). TAMs from these anatomical sites were clearly distinguishable by polarization states, with omTAMs exhibiting a mixed M1⁺/M2⁺ phenotype, in contrast to the M1low/M2⁺ profile observed in ascTAMs. Transcriptomic analysis further revealed functional divergence of these subsets. Notably, omTAMs displayed gene signatures associated with mesothelial-to-mesenchymal transition (MMT), a critical process enabling tumor invasion across the peritoneal lining. Functionally, conditioned media from omTAMs, similar to that from classically activated M1 macrophages, induced MMT in primary mesothelial cells via TGFβ and ERK/p38 MAPK signaling pathways. This phenotypic transition enhanced transmesothelial tumor cell invasion. Proteomic analysis identified IL-1α as a key MMT-inducing factor secreted by pro-inflammatory macrophages. Mechanistically, IL-1α cooperates with TGFβ by activating an autocrine TGFβ/TGFBR1 feedback loop in mesothelial cells, thereby amplifying MMT. Consistent with these findings, IL1A expression was enriched in omTAM clusters across independent patient samples and was confirmed by immunohistochemical analysis of clinical samples. From a therapeutic perspective, our study identifies new avenues to counteract the mesothelial reprogramming driven by IL-1α⁺ TAMs, potentially impeding metastatic progression. Created in BioRender. Heidemann, S. (2026) https://BioRender.com/aeu6yd0 .

Female↗
PubMed2026

Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort.

The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the Penelope-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and messenger RNA (mRNA) profiles, including HER2 transcripts. In Penelope-B, 57.68% (n = 417) of 723 residual tumors were HER2 low. The HER2-ultralow category was assigned to 109 (15.08%) tumors, and 197 (27.25%) tumors were completely HER2 negative (HER2 0). In Kaplan-Meier analysis, there were no survival differences among these 3 subgroups. There was no significant difference in HER2 mRNA expression between HER2-0 and HER2-ultralow tumors (P = .08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (P < .0001) and between HER2-low and HER2-positive tumors (P < .0001). The extracellular protease cathepsin L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups and was a negative prognostic factor for invasive disease-free survival and overall survival (P = .0001) in preneoadjuvant core biopsies. In our study, we were able to characterize HER2 low as a clinically relevant and molecular defined tumor group with significantly increased HER2 expression. In contrast, for HER2 ultralow, we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultralow subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility.

Adult↗
PubMed2025

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

Humans↗