Dario C. Altieri, M.D.
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
A third 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.