Shukla Research Lab
To unravel the molecular basis of asbestos-induced diseases including mesothelioma and lung cancer and develop therapeutic strategies.
Overview of current areas of research and approaches
Signaling pathways in mesothelioma:
(NCI/NIH and MARF supported work)
- Our long-term research interests have been in studying cell signaling mechanisms of asbestos fiber-induced lung diseases including cancer and mesothelioma.
- These mechanisms are explored in
- human mesothelial cells
- different mesothelioma cell lines
- patient derived samples
- animal models
- Potential pathways to be targeted by different anti-cancer drugs in combination with pathway inhibitors
- ERK cell signaling role in development of malignant mesothelioma (MM)
- ERK 1, 2 & 5 and CREB are very important in mesothelioma pathogenesis
- follow-up preclinical trial with ERK5 specific inhibitor XMD8-92
Inflammasomes in the pathogenesis of mesothelioma:
- NIH/NIEHS funding to study the role of inflammation with special emphasis on inflammasomes in MM pathogenesis
- NLRP3 inflammasome plays a significant role in development of asbestos-induced mesothelioma.
- Use of mesothelioma cancer and xenograft mouse models demonstrated that combination of cisplatin with IL-1 receptor antagonist works better to slow tumor growth.
- Assessing differential susceptibility of pleural and peritoneal mesothelial cells to asbestos utilizing Next Gen (Massive Parallel) sequencing with UVM Cancer Center financial support helped us to understand in part why pleural mesothelioma is more common than peritoneal mesothelioma.
Exosomes in development and therapy of mesothelioma:
- Department of Defense funding has allowed us to explore the role(s) of exosomes
- Exosomes are carriers of information from asbestos exposed epithelial cells or macrophages to mesothelial cells for development of MM.
- MM tumor cells lose tumor suppressor miRNA via exosomes. Inhibition of exosome secretion or force-feeding exosomes back could be an effective strategy to slow MM tumor growth.
- Exosome protein signature can be used as biomarkers for early diagnosis of MM (and other cancers).
Inflammasome and unfolded protein response interaction in development of lung fibrosis and mesothelioma
- NIH/NIEHS funded study
- Unfolded proteins response (UPR) regulates NLRP3 inflammasome activation in mesothelial cells in response to asbestos/carbon nanotubes (CNT) exposure. Specific deletion of UPR, IE1a from mesothelial cells had no significant impact on CNT-induced lung fibrosis in mice.