Biology subjects

Rask, G.

Publications and source records attributed to Rask, G..

3 recordsLinked to original sources

bioRxiv2022

Collagen XVIII promotes breast cancer through EGFR/ErbB signaling and its ablation improves the efficacy of ErbB-targeting inhibitors

The tumor extracellular matrix (ECM) is a critical regulator of cancer progression and metastasis, significantly affecting the treatment response. Expression of collagen XVIII (ColXVIII), a ubiquitous component of basement membranes, is induced in many solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII is markedly upregulated in human breast cancer (BC) cells and is closely associated with a poor prognosis in high-grade BC, especially in human epidermal growth factor receptor 2 (HER2)-positive and basal/triple-negative cases. We identified a novel mechanism of action for ColXVIII as a modulator of epidermal growth factor receptor (EGFR/ErbB) signaling and show that it forms a complex with EGFR, HER2 and 6 integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/Akt cascades. In vivo studies with Col18a1 mouse models crossed with the MMTV-PyMT mammary carcinogenesis model showed that the short ColXVIII isoform promotes BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in both mouse and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII in human BC cells and the MMTV-PyMT model substantially improved the efficacy of certain EGFR/ERbB-targeting therapies, even abolishing resistance to EGFR/ErbB inhibitors in some cell lines. In summary, a new function is revealed for ColXVIII in sustaining the stemness properties of BC cells, and tumor progression and metastasis through EGFR/ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have significant therapeutic potential. One Sentence SummaryCollagen XVIII is upregulated in breast cancer and promotes mammary carcinogenesis through EGFR/ErbB signaling and by sustaining cancer stem cells, so that its targeting improves the efficacy of ErbB-targeted therapies.

cancer biology↗

bioRxiv2021

Mitochondrial Dysfunction is a Driver for SP-2509 Drug Resistance in Ewing Sarcoma

Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine specific demethylase-1 (LSD1) inhibitors, which are currently in early phase clinical trials. Single agent targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP- 2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents which prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.

cancer biology↗

bioRxiv2021

Selective Modulator of Nuclear Receptor PPARy with Reduced Adipogenic Potential Ameliorates Experimental Nephrotic Syndrome

BackgroundGlomerular disease, often manifesting as nephrotic syndrome (NS) with high proteinuria, can be refractory to standard treatment and is typically associated with hypoalbuminemia, hypercholesterolemia and hypercoagulopathy. We hypothesized that the nuclear receptor PPAR{gamma} can be selectively modulated using a novel partial agonist, GQ-16, to gain therapeutic advantage over traditional PPAR{gamma} agonists (e.g. thiazolidinediones) for the treatment of glomerular disease. MethodsNephropathy was induced with puromycin amino-nucleoside (PAN) in Wistar rats and treated with Pioglitazone (Pio) or GQ-16. Plasma, serum, and urine chemistries were performed, and kidneys, glomeruli, liver, and white adipose tissue (WAT) were harvested. Lipid accumulation and adipogenic gene expression were measured in adipocytes. ResultsPAN-induced proteinuria was significantly reduced with Pio to 64% of PAN-value. It was reduced robustly with GQ-16 to 81% of PAN, which was comparable to controls. While both GQ-16 and Pio restored glomerular Nphs1 and hepatic Pcsk9 expression and reduced hypercholesterolemia, GQ-16 also restored glomerular Nrf2, and reduced hypoalbuminemia and hypercoagulopathy. Furthermore, RNA-seq analysis identified both common and distinct restored glomerular genes downstream of Pio and GQ-16. Pio but not GQ-16 significantly induced aP2 (fatty acid binding protein) in adipocytes and in WAT. Pio induced more lipid accumulation than GQ-16 in differentiated adipocytes. Both, Pio and GQ-16 induced insulin sensitizing adipokines in WAT with varying degrees. ConclusionsSelective modulation of PPAR{gamma} by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria and NS associated co-morbidities, while reducing the adipogenic side-effects conferred by traditional PPAR{gamma} full agonists. Translational StatementThe authors have previously reported that type-II diabetes drugs, thiazolidinediones (PPAR{gamma} agonists), also provide beneficial effects in reducing podocyte and glomerular injury. However, these drugs are associated with adverse effects such as weight gain, and their effects on glomerular disease-associated features are largely unexplored. Their current findings demonstrate that PPAR{gamma} can be selectively modulated by its partial agonist, GQ-16, which reduces proteinuria and improves nephrotic syndrome (NS) with reduced side-effects typically conferred by thiazolidinediones. These findings not only deepen our molecular understanding of the role of PPAR{gamma} in glomerular disease and underscore the potential for partial agonists of PPAR{gamma}, such as GQ-16 as a treatment modality for NS, but also lend the possibility of its potential benefits in diabetic nephropathy.

molecular biology↗