Biology subjects

Wickenhauser, C.

Publications and source records attributed to Wickenhauser, C..

4 recordsLinked to original sources

bioRxiv2026

Targeting poorly differentiated thyroid cancer with bispecific antibodies and CAR T cells from the human anti-TSHR autoantibody repertoire

Background: Poorly differentiated thyroid carcinoma (PDTC) has no effective systemic treatment option once radioactive iodine and tyrosine kinase inhibitors fail. The thyroid-stimulating hormone receptor (TSHR) is highly tissue-restricted and the anti-TSHR autoantibody repertoire of thyroid autoimmunity offers sequence-defined, fully human binders. We asked whether this repertoire can be converted into an off-the-shelf T cell-redirecting therapy for PDTC. Methods: TSHR expression was profiled on a 151-case thyroid cancer tissue microarray (TMA), 50 healthy controls and on fresh tumor material. Eight anti-TSHR clones, four of human autoimmune origin (M22, K1-18, K1-70, 5C9) and four murine (IRI-SAb2, IRI-SAb3, 9D33, 1H7), were reformatted as CD3-engaging bispecific antibodies (bsAbs; anti-TSHR Fab x anti-CD3 scFv) and, for leading clones, as chimeric antigen receptor (CAR) T cells. Activity was compared in vitro, across graded and mixed antigen densities and in a CAL-62-Luc-TSHR xenograft model, using healthy-donor (HD) or thyroid cancer-patient T cells. Results: TSHR was retained on a substantial fraction of PDTC, including metastatic lesions. Both formats mediated potent, antigen-selective killing and the leading bsAbs suppressed xenograft growth in vivo. For CAR T cells, scFv heavy/light-chain orientation was decisive. Anti-TSHR bsAbs cleared mixed cultures far beyond the antigen-positive fraction matching mosunetuzumab and indicating a modality-intrinsic bystander effect. Patient-derived T cells obtained on or after oncological treatment retained full effector function. Conclusions: The anti-TSHR autoantibody repertoire provides a promising source of binders for off-the-shelf bispecific antibodies targeting TSHR-positive thyroid cancer, while CAR T cells offer an autologous alternative.

cancer biology↗

bioRxiv2023

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

The long-term consequences of cancer or cancer therapy on the patients immune system years after cancer-free survival remain poorly understood. Here, we have performed an in-depth characterization of the bone marrow ecosystem of multiple myeloma long-term survivors at initial diagnosis and up to 17 years following cancer-free survival. Using comparative single-cell analyses in combination with molecular, genomic and functional approaches, we demonstrate that multiple myeloma long-term survivors display pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently driven by an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible immunological scarring caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of multiple myeloma long-term survivors, revealing reversible and irreversible alterations of the immune compartment, which can serve as diagnostic and predictive tools. Statement of significanceLarge-scale single-cell profiling of a unique cohort of multiple myeloma long-term survivors uncovered that exposure to cancer and its treatment causes both reversible and irreversible immune alterations associated with impaired immunity. These findings have far-reaching implications for the understanding of long-term immune alterations in cancer, which need to be considered also in the context of immune therapeutic approaches. Furthermore, our study demonstrates how cancer-associated immune trafficking can be used to predict disease re-initiation in the bone marrow, opening new avenues for minimally invasive disease monitoring.

cancer biology↗

bioRxiv2022

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

Inter-patient variability and the similarity of healthy and leukemic stem cells have impeded the characterization of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. While residual healthy cells dominated the dormant stem cell compartment, active leukemic stem cells resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors were highly aberrant and constituted the disease-defining compartment: Their gene expression and differentiation state determined both chemotherapy response and the leukemias ability to differentiate to transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers mis-regulated specifically in leukemic cells by intra-patient comparisons. Taken together, CloneTracer revealed a differentiation landscape that mimics its healthy counterpart and determines biology and therapy response in AML.

cancer biology↗

bioRxiv2020

IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HG-SOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here we show, that the IGF2 mRNA binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HG-SOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in a RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signaling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rational for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HG-SOC. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cancer biology↗