Biology subjects

Oppelt, A.-S.

Publications and source records attributed to Oppelt, A.-S..

4 recordsLinked to original sources

bioRxiv2026

Intratumoral expression of JAML on NK cells is controlled by tumor microenvironment and MHC class I interaction

Junctional adhesion molecule-like (JAML) is an adhesion molecule known to promote T cell activation and T cell-mediated tumor rejection. In the current study, we show that JAML expression is enriched on mouse intratumoral NK cells compared with splenic NK cells. JAML+ NK cells were associated with tissue residency and co-expressed the immune checkpoints PD-1 and LAG3. JAML expression could be induced on splenic NK cells by IL-2 and further enhanced by IL-21. JAML levels were inversely correlated with inhibitory signaling, as NK cells expressing self-recognizing Ly49 receptors had reduced JAML expression, suggesting regulation of JAML expression by MHC class I molecules. Interaction with the JAML ligand CXADR also reduced JAML surface expression, indicating that tumor-mediated membrane stripping may represent a mechanism of immunoediting. Although JAML RNA transcripts were detectable in human NK cells, JAML protein was found only intracellularly. Together, these findings identify the JAML-CXADR interaction as a potential regulatory pathway in NK cell-mediated killing of tumors.

immunology↗

bioRxiv2026

ALK R1275Q mutation drives expansion of SCP-like cells during sympathoadrenal commitment and primes neuroblastoma initiation.

Neuroblastoma (NB) is a pediatric malignancy developing in the sympathoadrenal lineage of the neural crest, characterized by clinical heterogeneity ranging from spontaneous regression to poor outcomes. Activating mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) are frequently observed in both sporadic and familial NB, yet the functional role of ALK in tumor initiation is not fully understood. Using a patient-derived human induced pluripotent stem cell (iPSC) model of sympathoadrenal development, we show that upon sympathoadrenal lineage commitment, ALK R1275Q, the most common hotspot mutation found in familial NB, sustain a proliferative, immature Schwann cell precursor (SCP)-like cell state with elevated ALK signaling and increased susceptibility to MYCN-driven transformation. While ALK-mutant cells alone did not form tumors in vivo, they cooperated with MYCN to accelerate tumor initiation, suggesting that ALK R1275Q creates a permissive but insufficient state for transformation. These findings define an ALK-driven cell progenitor-like state that facilitates the initiation of NB during embryonal development.

cancer biology↗

bioRxiv2025

Mice carrying nonsense mutant p53 develop spontaneous tumors with frequent metastases

The TP53 tumor suppressor gene is mutated in a large fraction of human tumors. Close to 11% of TP53 mutations are nonsense mutations, causing premature termination of protein synthesis and expression of truncated inactive p53 protein. The most common TP53 nonsense mutation in human cancer is R213X. To study the impact of TP53 nonsense mutations in vivo, we generated mice harboring the Trp53 nonsense mutation R210X that corresponds to human TP53-R213X. Initially, Trp53R210X mice appear phenotypically normal, although the proportion of female Trp53R210X/R210X mice is dramatically reduced. Female homozygous mice are poor breeders and remain smaller and lighter than female heterozygous and wildtype littermates. Trp53R210X/R210X mice start to show tumors at 2.5 months of age, and their maximal lifespan is 8.5 months. Trp53R210X/+ mice present tumors from 9 months of age, and by 16.5 months of age 50% of all heterozygous mice have developed overt tumors. 71% of tumors from Trp53R210X/+ mice show loss of heterozygosity (LOH). Homozygous mice develop hematopoietic and mesenchymal tumors, most commonly T-cell lymphoma and leiomyosarcoma, and heterozygous mice develop hematopoietic, mesenchymal, epithelial and sex cord tumors, most commonly osteosarcoma and leiomyosarcoma. The tumor phenotype is similar to that of Trp53-null and Trp53-missense knock-in mice, although the Trp53R210X/R210X mice have a high rate of multicentric or metastatic tumors, and Trp53R210X/+ mice have a longer overall survival than Trp53R172H/+ missense mutant knock-in mice. Treatment of T-cell lymphoma cells from Trp53R210X/R210X mice with aminoglycoside G418 induces expression of full-length functional p53 and apoptotic cell death. Our new unique mouse model will allow further studies of the effects of Trp53 nonsense mutation in a multi-organ system and serve as a model for the Li-Fraumeni syndrome (LFS). It will also be valuable for preclinical evaluation of novel therapeutic strategies for targeting TP53 nonsense mutations in cancer.

cancer biology↗

bioRxiv2024

Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing.

Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development; however, they may not be suitable for high-throughput screening efforts. We demonstrate here that transplantation of seven different MB cell lines or patient-derived cells into the blastula stage of zebrafish embryos leads to orthotopic tumor cell growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal progenitor phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB xenograft model has the potential to be used for high-throughput drug screening. Key pointsO_LIMedulloblastoma cells home to the hindbrain region in developing zebrafish embryos. C_LIO_LINeural stem cell culture conditions improve the homing capacity of MB tumor cells. C_LIO_LIMedulloblastoma-transplanted zebrafish embryos can be used as a high-throughput in vivo model for drug screening. C_LI Importance of the StudyOne of the challenges of accurately modeling medulloblastoma is the large heterogeneity in tumor characteristics. To accurately model this heterogeneous disease, patient-derived xenograft mouse models are currently the standard. However, such mouse models are labor intensive, time-consuming, and not suitable for high-throughput studies. Here, we describe a quick and straightforward zebrafish xenograft model that provides a promising alternative to these existing mouse models. We demonstrate that this model can be utilized to study tumor cell growth of several major medulloblastoma subgroups. More importantly, our model facilitates high-throughput drug testing, providing a scalable opportunity for in vivo drug screenings that will support the discovery of novel therapeutic compounds against medulloblastoma.

cancer biology↗