Biology subjects

Malinova, A.

Publications and source records attributed to Malinova, A..

4 recordsLinked to original sources

bioRxiv2023

ecDNA amplification of MYC drives intratumor copy-number heterogeneity and adaptation to stress in PDAC

Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here, we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNA can drive exceptionally high dosage of MYC and afford cancer cells rapid adaptation to microenvironmental changes. The continued maintenance of extrachromosomal MYC is uniquely ensured by the presence of the selective pressure. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors, with the highest MYC levels correlating with squamous-like phenotypes. Our work provides the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.

cancer biology↗

bioRxiv2023

The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few available therapeutic options. Two transcriptional cancer cell states have been consistently reported in PDAC, with the basal-like/squamous phenotype displaying a more aggressive biological behavior. Genetic and epigenetic dysregulation of the axon guidance pathway are common in PDAC, yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in sustaining the progression of PDAC. We integrated available transcriptomic datasets of human PDAC with in situ hybridization analyses of patients tissues to find that SEMA3A is expressed by stromal cells and selectively enriched in epithelial cells of the basal-like/squamous subtype. We found that both cell-intrinsic and cell extrinsic factors instructing the basal-like/squamous subtype induce expression of SEMA3A in PDAC cells. In vitro, SEMA3A promoted cell migration as well as anoikis resistance. At molecular level, these phenotypes were associated with increased FAK signaling and enrichment of gene programs related to cytoskeleton remodeling. Accordingly, SEMA3A provided mouse PDAC cells with greater metastatic competence. In mouse orthotopic allografts, SEMA3A remodeled the TME by favoring infiltration of tumor-associated macrophages and exclusion of T cells. Mechanistically, SEMA3A functioned as chemoattractant for macrophages and favored their polarization towards an M2-like phenotype. In SEMA3Ahigh tumors, depletion of macrophages resulted in greater intratumor infiltration by CD8+ T cells and increased sensitivity of these tumors to chemotherapy. Overall, we show that SEMA3A contributes to the malignant phenotype of basal-like PDAC.

cancer biology↗

bioRxiv2022

Increased early sodium current provokes familial atrial fibrillation and reduces effectiveness of sodium channel block

(1) AimsAtrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the -subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF. (2) MethodsWe designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, ECG, echocardiography, gravimetry, histology and biochemistry. (3) ResultsAtrial cardiomyocytes from newly generated adult Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/- mice could be excluded. (4) ConclusionThe Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability and thus AF. Whats newO_LIThe point mutation M1875T in the C-terminal domain of the cardiac sodium channel Nav1.5 causes an increase in early peak sodium current in left atria. C_LIO_LIThe observed changes induced by this point mutation suggest an increase in peak sodium current as a cause of familial atrial fibrillation (AF). C_LIO_LIOur findings provide a possible explanation for the variable effectiveness of sodium channel blockers in patients with AF. Carriers of such sodium channel gain-of-function mutations may benefit more from tailored treatments. C_LI Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

molecular biology↗

bioRxiv2019

Tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

A disintegrin and metalloprotease 10 (ADAM10) is essential for embryonic development and impacts on diseases such as cancer, Alzheimers and inflammatory diseases. ADAM10 is a molecular scissor that proteolytically cleaves the extracellular region from over 100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors and chemokines. ADAM10 was recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function is critically dependent on a TspanC8 partner. To address this, we generated the first monoclonal antibodies to Tspan15 as a model TspanC8. These were used to show that ADAM10 is the principal Tspan15-interacting protein, that Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Together these findings suggest that ADAM10 exists as an intimate ADAM10/TspanC8 scissor complex.

cell biology↗