Biology subjects

Hoser, G.

Publications and source records attributed to Hoser, G..

3 recordsLinked to original sources

bioRxiv2025

Renal cancer cell-derived amphiregulin recruits mesenchymal stromal cells, induces their glycolytic switch, and promotes tumour growth

Mesenchymal stem/stromal cells (MSCs) are multipotent cells that support wound healing. Tumours, often called as wounds that do not heal, recruit MSCs, which in turn support tumour growth. The immunomodulatory MSCs properties are facilitated under hypoxic conditions, while tumours are often hypoxic and immune-suppressed. It is unclear how MSCs wound healing actions are prevented in tumours. Here, we found that renal cancer cells secrete amphiregulin which induces MSCs recruitment and facilitates tumour growth in vivo. In MSCs, AREG triggers HIF1A degradation and transcriptional reprogramming, leading to glycolytic switch, increased migration and attenuation of immunoregulatory profile. In renal cancer cells, AREG stimulates expression of oncogenic proteins, including AKR1C3, leading to increased tumour growth and angiogenesis. To our knowledge, this is the first study showing that glycolytic switch in MSCs is induced by cancer. Our study provides insight into how renal cancer cells attenuate MSCs wound pro-healing properties to facilitate tumour growth.

cancer biology↗

bioRxiv2023

SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1α in pulmonary epithelial and endothelial cells

Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger cell death and IL-1 release from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1 and IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1 as a potential novel component driving the pulmonary immunothromobosis in COVID-19.

immunology↗

bioRxiv2021

Targeting Integrated Stress Response by ISRIB combined with imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells

Integrated Stress Response (ISR) facilitates cellular adaptation to variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CM Blast Crisis (BC) D34+ resistant cells. We found that in Patient Derived Xenograft (PDX) mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFN{gamma} pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation.

cancer biology↗