Biology subjects

Lehrstrand, J.

Publications and source records attributed to Lehrstrand, J..

3 recordsLinked to original sources

bioRxiv2025

Deep tissue optical 3D imaging reveals preferential preservation of extra-islet β-cells in late-onset Type 1 Diabetes

As residual {beta}-cell function may have positive effects on diabetes regulation in T1D, details on its spatial distribution and mass could provide important information for potential future therapeutic regimens. We implemented an optical 3D imaging pipeline to generate a first account of the 3D-spatial and volumetric distribution of the remaining {beta}-cells throughout the volume of an entire human late onset T1D pancreas at a microscopic resolution. As expected, {beta}-cell mass was dramatically lower than in the non-diabetic pancreas. However, the pancreatic head displayed a morphology and size resembling the non-diabetic pancreas and had a 3 times higher {beta}-cell density compared to the rest of the organ. Surprisingly, only a fraction of the residual {beta}-cells were located within islet structures. Instead, the absolute majority were present as extra-islet {beta}-cells, either as scattered individual cells or as clusters of {beta}-cells, spatially separated from all other endocrine cell-types. Jointly, these extra-islet {beta}-cells appeared roughly 60x less prone to succumb than islet associated {beta}-cells. In sharp contrast to {beta}-cell mass, -cell density appeared unaffected. This 3D whole organ depiction of an entire long standing, late onset, T1D pancreas shows that individual {beta}-cells may be preserved in a highly regionalized manner, potentially reflecting key aspects of disease dynamics.

pathology↗

bioRxiv2025

Podoplanin-Linked Mesenchymal Shift Synergizes with CCR7 driving Lymphatic Metastasis and Tumor Progression in Breast Cancer

Epithelial-to-mesenchymal-transition (EMT) and upregulation of chemokine receptors are linked to lymphatic metastasis in various types of cancer including breast cancer. However, the underlying molecular mechanisms are not fully understood. Using a triple-negative mammary carcinoma model, conditioned for lymphatic metastasis through expression of the C-C chemokine receptor 7 (CCR7), we identified intrinsic tumor plasticity associated with EMT as a critical determinant for effective metastasis. Specifically, tumor cells upregulate Podoplanin (PDPN) as part of a spontaneous mesenchymal shift that promotes lymphatic dissemination and tumor growth. Intriguingly, the expression of CCR7, or PDPN alone, was not sufficient for these effects. CCR7- and PDPN-positive tumors displayed an immune-cold tumor profile, compared to control, characterized by reduced tumor-infiltrating T-cells. Consistent with this, we found that spontaneous upregulation of PDPN was linked to hypoxia and was associated with the downregulation of homeostatic interferon signaling, and increased expression of collagens. Analysis of single-cell data sets showed that PDPN expression was heterogeneous and correlated significantly with EMT markers, collagen expression, and hypoxia hallmark in human breast cancer cell lines and primary human triple negative (TN) breast cancer, mirroring findings in the mouse model. Further analysis of the human breast cancer METABRIC-microarray datasets supported an association between a high CCR7/PDPN mRNA expression score and aggressive breast cancer subtypes with an independent prognostic value in lymph node-positive tumors. Together, these findings highlight a critical role of tumor microenvironment-driven tumor plasticity and molecular synergy between CCR7 and PDPN-coupled EMT shift in promoting chemokine receptor-mediated tumor dissemination and progression. SummaryCCR7-driven lymphatic metastasis requires a mesenchymal shift with PDPN upregulation. This tumor plasticity, linked to hypoxia and immune evasion, suggests CCR7-PDPN synergy in aggressive breast cancer progression and poor prognosis.

cancer biology↗

bioRxiv2023

Illuminating the complete β-cell mass of the human pancreas - signifying a new view on the islets of Langerhans

Pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis, but critical information regarding their mass, distribution and composition is lacking within a whole organ context. Here, a new 3D imaging pipeline was applied to generate a first complete account of the insulin-producing islets throughout the human pancreas at a microscopic resolution and within a maintained spatial 3D context. These data show that human islets are far more heterogenous than previously accounted for with regards to their size distribution and cellular make up. By deep tissue 3D imaging, this in-depth study demonstrates that 50% of the human insulin-expressing islets are virtually devoid of glucagon-producing a-cells, an observation with significant implications for both experimental and clinical research. One Sentence Summary: New islet heterogeneity identified in the human pancreas

cell biology↗