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Dario Altieri, M.D.

Dario C. Altieri, M.D.

Laboratory

The Altieri Laboratory

Contact

215-898-3774
mcolelli@wistar.org

President & Chief Executive Officer

Director, The Wistar Institute Cancer Center

Robert & Penny Fox Distinguished Professor

Professor, Immunology, Microenvironment & Metastasis Program

About the Scientist

Altieri is interested in how tumor cells evade the normal processes that cause cells with genetic faults to self-destruct. Understanding these mechanisms could provide new therapeutic targets and novel approaches for virtually every type of human cancer.  

Born in Milan, Italy, and educated at the University of Milan School of Medicine, Altieri became a practicing clinician at the University, where he would later earn a postgraduate specialty degree in clinical and experimental hematology. In 1987, he joined the Scripps Clinic and Research Foundation in La Jolla, California, first as a research fellow and later as a member of the faculty. 

In 1994, Altieri became an associate professor at the Yale University School of Medicine, was named professor in 1999, and served in that role until 2002 when he was recruited as the founding chair of the Department of Cancer Biology at the University of Massachusetts Medical School.  Altieri joined the Institute as the Wistar Cancer Center Director and its first Chief Scientific Officer in September 2010. He was appointed as President and Chief Executive Officer of Wistar in 2015. 

View Publications

The Altieri Laboratory

The Altieri laboratory explores the mechanisms that underlie how tumor cells survive and proliferate in cancer. The lab also focuses on mechanisms of cellular adaptation by tumor cells, and how these processes promote resistance to treatment and acquisition of a more malignant phenotype. Current efforts focus on elucidating the role of molecular chaperones compartmentalized in mitochondria in regulating tumor bioenergetics, adaptation to cellular stress and cell survival.

Staff

Staff Scientist

Jagadish Ghosh, Ph.D.

Associate Staff Scientist

Jie (Jack) Li, Ph.D.
Jae Ho Seo, Ph.D.

Postdoctoral Fellows

Ekta Agarwal, Ph.D.
Yuan Wang, Ph.D.

Research

The line between cell survival and cell proliferation in cancer

Tumor cells are fundamentally different than normal, healthy cells. In tumors, the clockwork genetic mechanisms that control the life cycle of cells are entirely disrupted, a fact that may hold the key to defeating cancer. The Altieri laboratory is interested in how tumor cells evade apoptosis – also known as programmed cell death – which is the process that normally causes dysfunctional cells to self-destruct. Bypassing apoptosis is a hallmark of cancer, and medical science is eager to find new ways of “reprogramming” cancer cells to die.

The Altieri laboratory studies a family of genes, known as Inhibitors of Apoptosis (IAP) proteins.  Identified first in the Altieri laboratory in 1997, and the source of intense investigation since then with currently 5,000 citations in PubMed, survivin is the smallest member of the IAP gene family. Differently from all other proteins in this class, survivin is selectively over-expressed in virtually every human cancer where it signals more aggressive disease and unfavorable outcome. Mechanistically, survivin is a multifunctional protein, controlling cell proliferation, cell death, the cellular stress response and developmental pathways of tumor maintenance. Survivin is also a major determinant of drug resistance in cancer, and a viable target for novel cancer therapeutics.

Altieri and his team are currently focused on three programs to understand the biology of survivin with respect to cell cycle progression, in particular, mitosis, cell survival and the cellular stress response and how exploiting these pathways may provide new cancer therapeutics.

The role of survivin in cell division

Cells produce – or “express” – great quantities of survivin just before they undergo the process of cell division, also called mitosis. Upon expression in dividing cells, survivin is rapidly recruited to various aspects of the mitotic apparatus, the scaffolding of microtubules that serve to physically separate and sort the proper complement of chromosomes into each of the two new cells that result from mitosis. The Altieri laboratory has extensively used cell biological approaches to probe the function of survivin at cell division. For instance, the laboratory has unraveled multiple roles of survivin at cell division, all of which ensure that the physical act of cell division occurs properly.  

The ability of survivin to inhibit apoptosis

In addition to a critical role in cell division, it is also clear that survivin has a function in protecting cells from apoptosis and that this pathway is followed in nearly every human tumor. Altieri and his colleagues have used biochemical and genetic approaches to study the role of survivin in apoptosis inhibition, and how this process enables aberrant cell viability in tumors, as well as resistance to therapy. They have found that animals engineered to express survivin in the skin exhibit strong resistance to apoptosis induced by ultraviolet B irradiation and that these animals are more prone to develop aggressive skin cancers. Conversely, they have found that interfering with survivin expression in tumor cells is sufficient to trigger apoptosis, to enhance the efficacy of conventional anti-tumor treatment, and to exert potent anti-tumor activity in vivo.  

The role of mitochondrial chaperones in cellular adaptation and tumor metabolism

Another line of investigation in the Altieri laboratory focuses on the role of molecular chaperones of the Hsp90 family in controlling tumor adaptation, metabolic reprogramming and cell survival. Results published by the Altieri laboratory demonstrated that these molecules accumulate in mitochondria of tumor cells, where they physically interact with components of the organelle permeability transition as well as with a number of regulators of bioenergetics, including the control of protein production, lipid metabolism and ATP generation. These interactions are critical for cancer cells to adjust to environments chronically depleted of oxygen and nutrients and to maintain cell proliferation and resistance to apoptosis. The laboratory identified and characterized a novel class of small molecule Hsp90 inhibitors selectively targeted to mitochondria (Gamitrinib), and these agents are being actively pursued to probe the pathway of mitochondrial chaperone-dependent adaptation and as novel cancer therapeutics. Current scientific efforts aim at elucidating the function of mitochondrial Hsp90s in tumor bioenergetics, the regulation of the cellular stress response and the resistance to conventional and targeted anticancer regimens.