Sox2 is dispensable for primary melanoma and metastasis formation

Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation

Targeting triple-negative breast cancer cells with a β1-integrin binding aptamer

Targeted therapies have increased the treatment options for triple-negative breast cancer patients. However, the paucity of targetable biomarkers and tumor heterogeneity have limited the ability of precision-guided interventions to live up to their full potential. As affinity-targeting ligands, aptamers show high selectivity toward target molecules. Compared with antibodies, aptamers have lower molecular weight, increased stability during transportation, reduced immunogenicity, and increased tissue uptake. Recently, we reported discovery of the GreenB1 aptamer, which is internalized in cultured triple-negative MDA-MB-231 human breast cancer cells. We show that the GreenB1 aptamer specifically targets 01-integrin, a protein linked previously to breast cancer cell invasiveness and migration. Aptamer binds to 01-integrin with low nanomolar affinity. Our findings suggest potential applications for GreenB1guided precision agents for diagnosis and therapy of cancers overexpressing 01-integrin

Personalized PDAC chip with functional endothelial barrier for tumour biomarker detection: A platform for precision medicine applications

The study was financially supported by the Latvian Council of Science State Research Programme project "Smart Materials, Photonics, Technologies and Engineering Ecosystems" (VPP-EM-FOTONIKA-2022/1-0001). The Institute of Solid-State Physics, University of Latvia, as the Center of Excellence, has received funding from the European Union's Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART2.Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterised by poor survival rates and an increasing global incidence. Advances in the staging and categorization of pancreatic tumours, along with the discovery of functional mutations, have made precision treatments possible, which may lead to better clinical results. To further improve customized treatment approaches, in vitro models that can be used for functional drug sensitivity testing and precisely mimic the disease at the organ level are required. In this study, we present a workflow for creating a personalized PDAC chip utilising primary tumour-derived human pancreatic organoids (hPOs) and Human Umbilical Vein Endothelial Cells (HUVECs) to simulate the vascular barrier and tumour interactions within a PDMS-free organ-on-a-chip system. The patient PDAC tissue, expanded as tumour hPOs, could be cultured as adherent cells on the chip for more than 50 days, allowing continuous monitoring of cell viability through outflows from tumour and endothelial channels. Our findings demonstrate a gradual increase in cell density and cell turnover in the pancreatic tumor channel. Tumour-specific biomarkers, including CA-19.9, TIMP-1, Osteopontin, MIC-1, ICAM-1 and sAXL were consistently detected in the PDAC chip outflows. Comparative analyses between tissue culture plates and microfluidic conditions revealed significant differences in biomarker secretion patterns, highlighting the advantages of the microfluidics approach. This PDAC chip provides a stable, reproducible tumour model system with a functional endothelial cell barrier, suitable for drug sensitivity and secretory biomarker studies, thus serving as a platform for functional precision medicine application and multi-organ chip development. © 2024 The Authors --//-- This is an open-access article Karina Goluba, Vadims Parfejevs, Evita Rostoka, Kaspars Jekabsons, Ilze Blake, Anastasija Neimane, Annija Anete Ule, Roberts Rimsa, Reinis Vangravs, Andrejs Pcolkins, Una Riekstina, Personalized PDAC chip with functional endothelial barrier for tumour biomarker detection: A platform for precision medicine applications, Materials Today Bio, Volume 29, 2024, 101262, ISSN 2590-0064, https://doi.org/10.1016/j.mtbio.2024.101262 published under the CC BY-NC-ND licence.Latvian Council of Science State Research Programme VPP-EM-FOTONIKA-2022/1-0001; European Union's Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 739508, project CAMART2

Injury and stress responses of adult neural crest-derived cells

Multipotent neural crest cells can self-renew and give rise to a plethora of neural and non-neural cell types in the vertebrate embryo. Intriguingly, cells reminiscent of such neural crest stem cells (NCSCs) have also been isolated from various postnatal and adult neural crest (NC)-derived structures. However, it has been debated whether NCSC-like cells in the adult correspond to ‘in vitro artefacts’ emerging upon isolation or fulfil a physiological role in vivo. Here, we discuss recent findings indicating that in different adult NC derivatives, injury or stress responses induce a NCSC-like state, presumably by reprogramming differentiated cells such as Schwann cells. Thereby, injury or stress appear to endow NC-derived cells with the capacity to generate new cell types during the repair process; in addition, injury can activate a repair program in adult NC-derived cells, which promotes tissue repair or regeneration by paracrine signalling. Thus, there is increasing evidence that NCSC-like cells in NC derivatives represent an in vivo state implicated in distinct physiological functions in the adult organism

Injury-activated glial cells promote wound healing of the adult skin in mice

Cutaneous wound healing is a complex process that aims to re-establish the original structure of the skin and its functions. Among other disorders, peripheral neuropathies are known to severely impair wound healing capabilities of the skin, revealing the importance of skin innervation for proper repair. Here, we report that peripheral glia are crucially involved in this process. Using a mouse model of wound healing, combined with in vivo fate mapping, we show that injury activates peripheral glia by promoting de-differentiation, cell-cycle re-entry and dissemination of the cells into the wound bed. Moreover, injury-activated glia upregulate the expression of many secreted factors previously associated with wound healing and promote myofibroblast differentiation by paracrine modulation of TGF-β signalling. Accordingly, depletion of these cells impairs epithelial proliferation and wound closure through contraction, while their expansion promotes myofibroblast formation. Thus, injury-activated glia and/or their secretome might have therapeutic potential in human wound healing disorders

Nervu kores izcelsmes šūnu loma brūču dzīšanas procesā: promocijas darbs

Perifērā neiropātija, var ietekmēt traumētas ādas atveseļošanas norisi. Izmantojot peļu brūču dzīšanas modeli, kurā glijas šūnas ir ģenētiski iezīmētas, mēs novērojām, ka ādas bojājums izraisa Švāna šūnu aktivāciju un migrāciju no nerva šķiedrām uz ievainotajiem audiem. Analizējot aktivētās glijas šūnas, mēs konstatējām, ka tās sekretē virkni faktoru, kam iepriekš novērota saistība ar brūču dzīšanu, un, aktivējot TGFβ signālceļu, tie veicina miofibroblastu veidošanos. Glijas šūnu skaita samazināšanās Sox10 inaktivētā gēna pelēs kavēja brūces aizvēršanos. Pretēji tam, glijas šūnu skaita pieaugums stimulēja miofibroblastu veidošanos. Tādējādi aktivētām glijas šūnām vai to izdalītiem faktoriem piemīt terapeitiskais potenciāls, ko varētu izmantot ādas brūču dzīšanas uzlabošanai. Kā potenciālu glijas šūnu avotu mēs raksturojām no cilvēka dermas izdalītās šūnas un parādām, ka tām piemīt mezenhimālajām cilmes šūnām raksturīgās iezīmes un diferenciācijas potenciālsPeripheral neuropathies impair wound healing capabilities of the skin, revealing the importance of skin innervation for proper repair. We use mouse wound healing model and glial cell fate tracing techniques to show that injury promotes glial de-differentiation, cell re-entrance into the cell cycle, and dissemination from nerve bundles into the wound bed. Analysis of genetically traced cells demonstrated that injury-activated glia secrete factors associated with wound healing and promote myofibroblast differentiation by paracrine modulation of TGF-β signalling. Genetic depletion of these cells impairs epithelial proliferation and wound closure, while their genetic expansion promotes myofibroblast formation. Thus, injury-activated glia might have therapeutic potential in wound healing disorders. As potential glial cell source, we characterize human skin dermis-derived cells, demonstrate that they possess mesenchymal stem cell features and differentiation potential