Our group's research interest is driven by the sobering statistics presented by children with metastatic Ewing sarcoma (EwS). It leads us to ask questions like: What makes a cancer cell spread to a particular organ? How are the normal cells in that organ used by the cancer cells for their own growth? What mediates this communication between different cell types? We use patient-derived tumors and lung metastatic cell lines developed in the lab to probe these questions focusing on the following projects.

Projects

Primary tumor (top) and lung lesions derived from lung-metastatic cell lines (bottom)

Characterization and Targeting Signaling Pathways in Metastatic Ewing Sarcoma

It is becoming increasingly obvious that we must study the tumor biology not in isolation, but in the context of the body - both micro and macro. To circumvent the limitation that no immunocompetent mouse model for EwS is available, we integrated tumor intrinsic and microenvironmental factors by using novel lung-specific metastatic cell lines generated in our lab. In vitro co-culture and ex vivo pulmonary metastasis assays are used to mimic physiological conditions. Using multi-omics approaches incorporating proteomic analysis, secretome, and cytokine profiling, we have analyzed these lung metastatic cell lines. These, in conjunction with focused Nanostring transcriptomic analysis from paired primary and lung metastatic patient samples revealed upregulation of several key pathways. In this project we are analyzing a network of these pathways.

Transmission electron microscope image of an extracellular vesicle isolated from Ewing sarcoma cells.

Role of Tumor Derived Extracellular Vesicles in Ewing Sarcoma Growth and Metastasis

Extracellular vesicles, or EVs, including exosomes are one of the key mediators of tumor-stroma communication. They communicate between cells by transmission of macromolecules including RNA, miRNA, proteins, lipids, and metabolites. Recent studies in breast, prostate, melanoma, and lung cancer have shown enhanced aggressiveness and modulation of the tumor microenvironment through EV communication. These critical studies on the role of cancer associated fibroblasts and the role played by EVs in these communications resulting in the complex process of metastasis have not been investigated for EwS. To answer these critical questions, our laboratory has developed novel, lung specific, fluorescent labeled metastatic EwS cell lines in A673 and TC71 with fluorescent tagged exosomes to enable their trafficking and to investigate their role in Ewing sarcoma tumor growth and metastasis.

PAK4, a serine/threonine kinase with oncogenic properties is a nidus for critical signaling cascades including Ras/MAPK, Wnt, and PI3K signaling.

Dissecting and targeting PAK4 in Ewing sarcoma

In collaboration with Dr. Jason Yustein at the Emory University, we have recently identified that p21-activated kinases (PAKs) are activated and promote metastasis in Ewing sarcoma. PAKs are a family of serine/threonine kinases that regulate key cell processes involved in metastatic progression and drug resistance and are imminently emerging as candidate anti-cancer targets. PAK4 is significantly overexpressed in metastatic EwS, and is negatively correlated with patient outcomes. Molecular and pharmacological perturbations of PAK4 in EwS models demonstrated significant anti-tumor and anti-metastatic activity. We also have preliminary evidence that PAK4 is a novel regulator of alternative splicing. In this project, we will examine PAK4’s role as a novel regulator of alternative splicing and PAK4-mediated downstream proteo-transcriptomic signatures that contribute to EwS progression.

Selected publications

Petrescu DI, Yustein JT, Dasgupta A. "Preclinical models for the study of pediatric solid tumors: focus on bone sarcomas.." Front Oncol.. 2024 Jul 18;14(1388484)
Atreyi Dasgupta, Lyazat Kurenbekova, Tajhal D Patel, Kimal Rajapakshe, Gargi Ghosal, Bikesh Nirala, Cristian Coarfa, Jason Yustein "Modeling Ewing Sarcoma Lung Metastasis." Curr Protoc.. 2023 Feb;3(2)
Dasgupta A, Sierra L, Tsang SV, Kurenbekova L, Patel T, Rajapakse K, Shuck RL, Rainusso N, Landesman Y, Unger T, Coarfa C, Yustein JT. "Targeting PAK4 Inhibits Ras-Mediated Signaling and Multiple Oncogenic Pathways in High-Risk Rhabdomyosarcoma.." Cancer Res.. 2021 Jan 1;81(1):199-212.
Shapiro MC, Tang T, Dasgupta A, Kurenbekova L, Shuck R, Gaber MW, Yustein JT. "In Vitro and In Vivo Characterization of a Preclinical Irradiation-Adapted Model for Ewing Sarcoma.." Int J Radiat Oncol Biol Phys. 2018 May 1;101(1):118-127.
Dasgupta A, Trucco M, Rainusso N, Bernardi RJ, Shuck R, Kurenbekova L, Loeb DM, Yustein JT. "Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties." Oncotarget. 2017 Aug 24;8(44):77292-77308.