Search

Background: Pancreatic cancer stands as one of the deadliest tumors, in part due to the limited efficacy of currently existing therapies. Pancreatic cancer is characterized at the genomic level by the almost universal presence of KRAS mutations. Phenotypically, it features an incipient desmoplastic stroma with a protein component formed by collagens, fibronectin and laminins. A member of the laminin family, LAMININ γ2 or LAMC2, was previously identified by our group as part of a cross-tumors KRAS signature whose high expression was a marker of poor survival in PDAC patients. While a role for LAMC2 in migration and invasion has been previously described, little is known about a potential function in cell proliferation and viability. Moreover, LAMC2 inhibition has been shown to enhance the activity of conventional chemotherapeutic agents. However, whether its abrogation can increase the effect of targeted therapies is yet to be defined. Finally, the direct relationship between LAMC2 and the KRAS oncogene network is yet to be defined. Methods: A meta-analysis of several human PDAC data sets and survival analysis of the TCGA data were performed to query the expression levels and prognosis significance of LAMC2. Human and mouse PDAC cell lines as well as a mouse model of PDAC (KrasLSLG12D, Tp53f/f, Ptf1aCre) were used to assess LAMC2 expression. In vitro (2D and 3D organoids) and in vivo models derived from human and mouse PDAC cell lines or primary tumors were used to define the functional role of LAMC2 in PDAC. Cellular and molecular analysis were deployed to dissect the mechanism of action of LAMC2 in PDAC. A dual pharmacological combination based on LAMC2-regulated effectors was also tested in human and mouse pancreatic cancer models. Results: At the clinical level, we observed that LAMC2 is overexpressed in human PDAC patients with regard to normal tissue. The overexpression of LAMC2 was recapitulated in human and mouse cell lines. Genetic depletion of LAMC2 had an adverse effect in 2D proliferation, clonogenic efficiency, 3D organoid growth, and PDAC-based xenograft/allograft tumor development. This deleterious effect was driven by an induction in apoptosis and a decrease in S phase consistent across species. Mechanistically, LAMC2 was linked to the KRAS pathway via transcriptional regulation of the transcription factor FOSL1/AP1, which was also a member of the cross-tumors signature. Furthermore, LAMC2 controlled a gene signature that overlaps with KRAS- and FOSL1-regulated gene signatures, which was also highly expressed in various pancreatic cancer data sets, and includes the targetable kinase AXL. Lastly, concomitant pharmacological inhibition of AXL and the FOSL1 upstream regulator MEK1/2 displayed a more adverse effect on human and pancreatic pancreatic cancer than each single drug alone. Conclusion: These data suggest that LAMC2 is a molecular target tightly linked to KRAS oncogene signaling that regulates downstream effectors amenable to the development of combination therapies. Citation Format: Shruthi Narayanan, Oihane Erice, Iker Feliu, Caterina Vicentini, Rodrigo Entrialgo-Cadierno, Karmele Valencia, Elisabet Guruceaga, Purvesh Khatri, Vicenzo Corbo, Silvestre Vicent Cambra, Mariano Ponz-Sarvise. Identification of a LAMC2-regulated network featuring targetable effectors for dual therapies in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-089.

Expression dynamics of basement membrane-like extracellular matrix and fibronectin regulate transitions between solid (moruloid) and cavitational (blastuloid) phenotypes of ovarian cancer spheroids., Ovarian cancer metastasizes into peritoneum through dissemination of transformed epithelia as multicellular spheroids. Harvested from the malignant ascites of patients, spheroids exhibit startling features of organization typical to homeostatic glandular tissues: lumen surrounded by smoothly contoured and adhered epithelia. Herein, we demonstrate that cells of specific ovarian cancer lines in suspension, aggregate into dysmorphic solid “moruloid” clusters that permit intercellular movement, cell penetration, and interspheroidal coalescence. Moruloid clusters subsequently mature into “blastuloid” spheroids with smooth contours, a temporally dynamic lumen and immotile cells. Blastuloid spheroids neither coalesce nor allow cell penetration. Ultrastructural examination reveals a basement membrane-like extracellular matrix coat on the surface of blastuloid, but not moruloid, spheroids. Quantitative proteomics reveals down-regulation in ECM protein Fibronectin-1 associated with the moruloid-blastuloid transition; immunocytochemistry also confirms the relocalization of basement membrane ECM proteins: collagen IV and laminin to the surface of blastuloid spheroids. Fibronectin depletion accelerates, and enzymatic basement membrane debridement impairs, lumen formation, respectively. The regulation by ECM dynamics of the morphogenesis of cancer spheroids potentially influences the progression of the disease.

The principal humic substances present in soils like Humic Acid (HA) and Fulvic Acid (FA) are plant fertility components many of which basically are aromatic in nature. Assaying these components is a challenge. The present study aims at an enquiry to delineate aromaticity of soil extracted HA and extracted FA by capturing their odor. Since these soil components are bound to soil particles, an effort has been put to find out whether they are more released in dry or wet soil conditions. The aromaticity determination was explored by Electronic nose (E-nose) equipment that had specific array of metal oxide sensors. The other objective of the study was to profile the aromaticity of HA and FA by their extraction from garden soil and its subsequent amendment. The series of experiments comprised of extraction of HA and FA and profiling of Norm Aroma Index (NAI) by E-nose in both wet and dry conditions of soil. The findings were that the yield of HA was more compared to FA; the NAI noted was high in wet condition of the soil compared to dry soil; HA showed more aromaticity compared to FA; the amended soil showed more aromaticity compared to non-amended normal soils. Among the amendment exercises, HA amended soil showed maximum aromaticity. E-nose employment could indicate extent of HA and FA in soils.

In this paper, the performance of iterative turbo coding with nonlinearly distorted orthogonal frequency division multiplexing (OFDM) signal is analyzed. System level implementation in Simulink is performed and bit error rate (BER) performance is analyzed. Initially, we have implemented both, the series turbo coder and iterative turbo coder, compared the performance and then using better performed iterative coder, model is implemented in Simulink. In the model, we introduced highly nonlinear distortion signal using solid state power amplifier (SSPA). It is observed that nonlinear distortion results in very high BER. However, BER performance is significantly improved by the use of iterative turbo coder. It is also seen that 6 iterations is found to be optimum. Higher or smaller iteration results in reduced performance.