Lab In The News
The emergence of Covid-19 has many scientists and life sciences industry CEOs shifting their priorities to battle the new coronavirus strain. Wistar’s researchers are in that mix, working with Plymouth Meeting’s Inovio on a DNA-based vaccine can
Cheyney U. Partners with The Wistar Institute for Life Science Program
Cheyney University and The Wistar Institute in Philadelphia have formed a partnership to expand life science research education, training and business development opportunities in Pennsylvania.
The Altieri Laboratory
The Altieri laboratory currently studies the role of mitochondria in cancer. The lab pursues the overarching hypothesis that multiple mitochondrial functions in bioenergetics, buffering of reactive oxidative species (ROS), inter-organelle communication with the endoplasmic reticulum (ER), and retrograde gene expression are invariably reprogrammed in malignancy and exploited to enable extraordinary plasticity and tumor heterogeneity for disease progression. Mechanistically, Altieri and his team have implicated these pathways in supporting tumor cell proliferation, evasion from multiple forms of cell death and, importantly, heightened tumor cell motility and invasion, leading to metastatic disease. To understand the role of tumor plasticity and mitochondrial reprogramming in disease progression and dissemination, Altieri uses a multidisciplinary collection of biochemical, cellular, and molecular approaches in vitro, xenograft, and genetic animal models of localized and metastatic disease, in vivo, and analysis of clinically-annotated primary patient samples. Although mechanistic in nature, Altieri lab research goals have clear translational and disease-relevant implications. Altieri’s work has demonstrated that therapeutic targeting of mitochondrial reprogramming in cancer is feasible, and may uniquely disable multiple mechanisms of disease progression, including metastatic competence across a broad spectrum of genetically heterogeneous tumors. Accordingly, a first-in-class, mitochondria-targeted small molecule inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90) was developed and characterized by the Altieri laboratory (Gamitrinib) and has recently entered first-in-human clinical trial in patients with advanced cancer (ClinicalTrials.gov NCT04827810).
Research Assistant Professors
Jagadish Ghosh, Ph.D.
Michela Perego, Ph.D.
Associate Staff Scientist
Irene Bertolini, Ph.D.
Woomyee Bae, Ph.D.
Minjeong Yeon, Ph.D.
Multifunctional Survivin Signaling in Cancer
The Altieri laboratory is credited with the discovery and characterization of the survivin gene. Approaching 9,500 citations currently in PubMed, survivin is recognized as a fundamental cancer gene, a pleiotropic molecular hub for multiple pathways of cell survival, mitosis, adaptation to stress and metabolic reprogramming, as well as a validated therapeutic target in the clinic. Altieri’s contributions in this field have run the gamut from the discovery of survivin to the characterization of its unique role at the interface between cell death and mitosis in cancer, to clinical validation as a therapeutic target and predictive/prognostic disease biomarker..
Mitochondrial Proteostasis in Tumor Adaptation
Over the past decade, the Altieri lab’s work uncovered a novel role of protein folding quality control in mitochondria as a key driver of tumor progression. These studies elucidated mechanisms of protein homeostasis, or proteostasis maintained by Heat Shock Protein-90 (Hsp90) chaperones as well as AAA+ proteases in mitochondria, characterized their role in adaptive regulation of apoptosis, metabolic reprogramming and retrograde gene expression, and identified novel mechanisms of tumor adaptation to microenvironment stress stimuli, including hypoxia or exposure to molecular therapy.
Mitochondria and Metastasis
How tumors that switch to an inefficient glycolytic metabolism, i.e. the Warburg effect, manage to accomplish highly energy-demanding tasks of cell motility and invasion has long remained elusive. Altieri’s work demonstrated that mitochondrial oxidative phosphorylation is required to fuel membrane dynamics of cell motility, resulting in increased tumor chemotaxis, invasion and metastasis. Mechanistically, Altieri showed that this pathway involves the redistribution of energetically active mitochondria to the peripheral cytoskeleton of tumor cells, where they provide a concentrated, spatiotemporal energy source to power membrane lamellipodia dynamics, turnover of focal adhesion complexes, and sustained phosphorylation of cell motility kinases.
Mitochondrial Control of Tumor Plasticity
Recent findings from the Altieri group have demonstrated that mitochondrial reprogramming is a universal cancer trait that imparts unique plasticity to a full spectrum of tumor responses, from early-stage malignant transformation to full blown tumor growth, to regulation of go-or-grow decisions, the dynamic and reversible switch between cell proliferation and cell migration states. The Altieri lab showed that mitochondrial control of tumor plasticity involves panoply of signaling pathways, including generation of ROS, exosome-dependent intercellular communication, and stabilization of HIF1 resulting in a transcriptionally-active, pseudo-hypoxic state.
Novel Cancer Drug Discovery Approaches
The Altieri laboratory has pioneered the concept of targeting mitochondrial reprogramming for novel cancer therapeutics. The group uses a combination of mitochondrial-targeted peptidomimetic antagonists and small molecule ATPase inhibitors to disrupt mitochondrial Hsp90-directed protein folding, inhibit oxidative bioenergetics and abolish MFF cytoprotection at the mitochondrial outer membrane. In preclinical studies, these first-in-class mitochondrial-targeted agents (Shepherdin, Gamitrinib, MFF 8-11) were well-tolerated, demonstrated a unique “mitochondriotoxic” mechanism of action, and delivered potent, cytotoxic anticancer activity alone or in combination with molecular therapies in localized and disseminated tumor models, in vivo.
Ghosh, J.C., Perego, M., Agarwal, E., Bertolini, I., Wang, Y., Goldman, A.R., Tang, H.Y., Kossenkov, A.V., Landis, C.J., Languino, L.R., et al. “Ghost Mitochondria Drive Metastasis Through Adaptive GCN2/AKt Therapeutic Vulnerability.” Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2115624119. doi: 10.1073/pnas.2115624119.
Agarwal, E., Goldman, A.R., Tang, HY., Kossenkov, A.V., Ghosh, J.C., Languino, L.R., Vaira, V., Speicher, D.W., Altieri, D.C. “A Cancer Ubiquitome Landscape Identifies Metabolic Reprogramming as Target of Parkin Tumor Suppression.” Sci Adv. 2021 Aug 25;7(35):eabg7287. doi: 10.1126/sciadv.abg7287. Print 2021 Aug.
Li, J., Agarwal, E., Bertolini, I., Seo, J.H., Caino, M.C., Ghosh, J.C., Kossenkov, A.V., Liu, Q., Tang, HY., Goldman, A.R., Languino, L.R., Speicher, D.W., et al. “The Mitophagy Effector FUNDC1 Controls Mitochondrial Reprogramming and Cellular Plasticity In Cancer Cells.” Sci Signal. 2020 Jul 28;13(642):eaaz8240. doi: 10.1126/scisignal.aaz8240.
Bertolini, I., Ghosh, J.C., Kossenkov, A.V., Mulugu, S., Krishn, S.R., Vaira, V., Qin, J., Plow, E.F., Languino, L.R., Altieri, D.C. “Small Extracellular Vesicle Regulation of Mitochondrial Dynamics Reprograms a Hypoxic Tumor Microenvironment.” Dev Cell. 2020 Oct 26;55(2):163-177.e6. doi: 10.1016/j.devcel.2020.07.014. Epub 2020 Aug 10.
Caino, M.C., Seo, J.H., Wang, Y., Rivadeneira, D.B., Gabrilovich, D.I., Kim, E.T., Weeraratna, A.T., Languino, L.R., Altieri, D.C. ”Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer.” J Clin Invest. 2017 Oct 2;127(10):3755-3769. doi: 10.1172/JCI93172. Epub 2017 Sep 11.
Mohamed Abdel-Mohsen, Ph.D.
Associate Professor, Vaccine & Immunotherapy Center
Immunology, Microenvironment & Metastasis Program, Ellen and Ronald Caplan Cancer Center