- Postdoc, Membrane biology; Harvard Medical School, Boston, MA
- Postdoc, Mitochondrial dynamics; University of Utah, Salt Lake City, UT
- Ph.D.; Cell and Molecular Biology; University of Vermont, Burlington, VT
- B.A.; Biology; College of our Lady of the Elms, Chicopee, MA
Department of Pathology and Laboratory Medicine
University of Vermont Cancer Center
Cellular, Molecular, and Biomedical Sciences Program
Areas of expertise
- How mitochondrial dynamics and metabolic function dictate cell processes including cell migration and tumor cell metastasis
- Developing novel therapies for the treatment of aggressive cancers such as malignant mesothelioma and ovarian cancer
BIO
My lab is investigating mitochondrial redox status as a therapeutic target in malignant mesothelioma (MM) and other aggressive tumors. Metabolic reorganization supports aggressive tumor growth while also leading to increased levels of mitochondrial reactive oxygen species (mROS), a metabolic byproduct of increased metabolism. In response, tumor cells upregulate their antioxidant capacity, including the mitochondrial antioxidant enzymes superoxide dismutase 2, thioredoxin 2 and peroxiredoxin 3 (PRX3), to survive and proliferate under otherwise inhospitable levels of mROS. Therefore, tumor cells are exquisitely sensitive to additional increases in mROS, providing a viable avenue of therapeutic intervention. As a graduate student, I showed that MM tumor cells are under increased oxidative stress, over-express the redox-dependent oncogenic transcription factor FOXM1, and the activity of mitochondrial antioxidant enzymes is increased compared to normal mesothelial cells. We also uncovered a novel mechanism of action of the anti-cancer compound thiostrepton (TS). TS irreversibly and covalently crosslinks the active-site cysteine residues of mitochondrial PRX3, inactivating its peroxidase activity and elevating mROS levels. Inactivation of PRX3 with TS induces cytotoxic mROS levels leading to cell death in numerous tumor cell models. As normal cells are under less mROS stress, they are significantly less sensitive to this approach, providing a therapeutic window for the selective killing of tumor cells. Our research supported the development and transition of TS to clinical trials for malignant mesothelioma and metastatic cancer associated with pleural effusion. TS is currently being evaluated in the MITOPE phase 1/2 multicenter trial (NCT05278975).
The second focus of my lab is on mitochondrial dynamics supporting cell migration and tumor cell metastasis. The subcellular positioning of mitochondria is essential for localized energy production; however, it is not known if perturbations in mitochondrial positioning have a direct effect on localized redox signaling networks that control cell fate decisions. We have provided direct evidence that subcellular reactive oxygen species (ROS) levels map directly to sites of increased mitochondrial density (Alshaabi et al. 2020). Loss of the mitochondrial adapter protein Miro1 restricts mitochondria to the perinuclear space and disrupts subcellular ROS gradients. To address the relationship between mitochondrial trafficking and cell phenotypes we received NIGMS funding to investigate how positioning of mitochondrial populations influences specific redox-dependent protein modifications, and thereby modulates protein phosphorylation, focal adhesion dynamics, membrane reorganization, cell migration and gene expression. Using a variety of novel genetic, biochemical, and imaging tools in vitro and in vivo, we seek to identify, characterize, and manipulate processes regulating mitochondrial dynamics in cell migration and as a potential therapeutic target in cancer.
Publications
Bio
My lab is investigating mitochondrial redox status as a therapeutic target in malignant mesothelioma (MM) and other aggressive tumors. Metabolic reorganization supports aggressive tumor growth while also leading to increased levels of mitochondrial reactive oxygen species (mROS), a metabolic byproduct of increased metabolism. In response, tumor cells upregulate their antioxidant capacity, including the mitochondrial antioxidant enzymes superoxide dismutase 2, thioredoxin 2 and peroxiredoxin 3 (PRX3), to survive and proliferate under otherwise inhospitable levels of mROS. Therefore, tumor cells are exquisitely sensitive to additional increases in mROS, providing a viable avenue of therapeutic intervention. As a graduate student, I showed that MM tumor cells are under increased oxidative stress, over-express the redox-dependent oncogenic transcription factor FOXM1, and the activity of mitochondrial antioxidant enzymes is increased compared to normal mesothelial cells. We also uncovered a novel mechanism of action of the anti-cancer compound thiostrepton (TS). TS irreversibly and covalently crosslinks the active-site cysteine residues of mitochondrial PRX3, inactivating its peroxidase activity and elevating mROS levels. Inactivation of PRX3 with TS induces cytotoxic mROS levels leading to cell death in numerous tumor cell models. As normal cells are under less mROS stress, they are significantly less sensitive to this approach, providing a therapeutic window for the selective killing of tumor cells. Our research supported the development and transition of TS to clinical trials for malignant mesothelioma and metastatic cancer associated with pleural effusion. TS is currently being evaluated in the MITOPE phase 1/2 multicenter trial (NCT05278975).
The second focus of my lab is on mitochondrial dynamics supporting cell migration and tumor cell metastasis. The subcellular positioning of mitochondria is essential for localized energy production; however, it is not known if perturbations in mitochondrial positioning have a direct effect on localized redox signaling networks that control cell fate decisions. We have provided direct evidence that subcellular reactive oxygen species (ROS) levels map directly to sites of increased mitochondrial density (Alshaabi et al. 2020). Loss of the mitochondrial adapter protein Miro1 restricts mitochondria to the perinuclear space and disrupts subcellular ROS gradients. To address the relationship between mitochondrial trafficking and cell phenotypes we received NIGMS funding to investigate how positioning of mitochondrial populations influences specific redox-dependent protein modifications, and thereby modulates protein phosphorylation, focal adhesion dynamics, membrane reorganization, cell migration and gene expression. Using a variety of novel genetic, biochemical, and imaging tools in vitro and in vivo, we seek to identify, characterize, and manipulate processes regulating mitochondrial dynamics in cell migration and as a potential therapeutic target in cancer.