Browsing by Author "Mishra, Dhruva K."

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    Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma
    (Public Library of Science, 2013) Baird, Brandi N.; Schliekelman, Mark J.; Ahn, Young-Ho; Chen, Yulong; Roybal, Jonathon D.; Gill, Bartley J.; Mishra, Dhruva K.; Erez, Baruch; OﾒReilly, Michael; Yang, Yanan; Patel, Mayuri; Liu, Xin; Thilaganathan, Nishan; Larina, Irina V.; Dickinson, Mary E.; West, Jennifer L.; Gibbons, Don L.; Liu, Diane D.; Kim, Min P.; Hicks, John M.; Wistuba, Ignacio I.; Hanash, Samir M.; Kurie, Jonathan M.
    The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-offunction experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wildtype littermates, implying that malignant progression was dependent specifically upon tumor cellderived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude
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    Transcriptional activators YAP/TAZ and AXL orchestrate dedifferentiation, cell fate, and metastasis in human osteosarcoma
    (Springer Nature, 2021) Lamhamedi-Cherradi, Salah-Eddine; Mohiuddin, Sana; Mishra, Dhruva K.; Krishnan, Sandhya; Velasco, Alejandra Ruiz; Vetter, Amelia M.; Pence, Kristi; McCall, David; Truong, Danh D.; Cuglievan, Branko; Menegaz, Brian A.; Utama, Budi; Daw, Najat C.; Molina, Eric R.; Zielinski, Rafal J.; Livingston, John A.; Gorlick, Richard; Mikos, Antonios G.; Kim, Min P.; Ludwig, Joseph A.
    Osteosarcoma (OS) is a molecularly heterogeneous, aggressive, poorly differentiated pediatric bone cancer that frequently spreads to the lung. Relatively little is known about phenotypic and epigenetic changes that promote lung metastases. To identify key drivers of metastasis, we studied human CCH-OS-D OS cells within a previously described rat acellular lung (ACL) model that preserves the native lung architecture, extracellular matrix, and capillary network. This system identified a subset of cells—termed derived circulating tumor cells (dCTCs)—that can migrate, intravasate, and spread within a bioreactor-perfused capillary network. Remarkably, dCTCs highly expressed epithelial-to-mesenchymal transition (EMT)-associated transcription factors (EMT-TFs), such as ZEB1, TWIST, and SOX9, which suggests that they undergo cellular reprogramming toward a less differentiated state by coopting the same epigenetic machinery used by carcinomas. Since YAP/TAZ and AXL tightly regulate the fate and plasticity of normal mesenchymal cells in response to microenvironmental cues, we explored whether these proteins contributed to OS metastatic potential using an isogenic pair of human OS cell lines that differ in AXL expression. We show that AXL inhibition significantly reduced the number of MG63.2 pulmonary metastases in murine models. Collectively, we present a laboratory-based method to detect and characterize a pure population of dCTCs, which provides a unique opportunity to study how OS cell fate and differentiation contributes to metastatic potential. Though the important step of clinical validation remains, our identification of AXL, ZEB1, and TWIST upregulation raises the tantalizing prospect that EMT-TF-directed therapies might expand the arsenal of therapies used to combat advanced-stage OS.