Acquired apoptotic resistance in 3D lung cancer spheroids
Initial Award Abstract
One important reason why cancers fail to respond to clinical treatments such as chemotherapy or radiotherapy is that cancers have a high resistance to apoptotic cell death, a form of programmed cell death. Discovering how cancers resist cell death could lead directly to steps that could bypass these survival defenses and help treatments to be more effective. When cells are studied in the laboratory, they are usually studied in flat 2D monolayers, where many mechanisms of resistance can be studied. However, solid tumors, such as lung, grow as 3D masses. When tumor cells grow into 3D structures, they can acquire an additional level of resistance, described as multicellular resistance. We believe that the study of the resistance acquired by cells in 3D may be valuable in improving clinical treatments. Indeed, acquisition by tumor cells of multicellular resistance may explain many instances in which treatments that are found to be effective in laboratories fail to work in the clinic. Lung cancer has indeed a high degree of resistance to various treatments. We have found effective strategies to induce apoptosis when the cells are grown in monolayers that fail when the cells are grown in small 3D structures called spheroids. We have now found that much of this resistance is located at the level of mitochondria, the main cellular organelle responsible of energetic metabolism.
Apoptosis is finely regulated by a subset of proteins belonging to the Bcl-2 family which interact with the mitochondria, regulating the stability of its membrane and functions. When sufficient death signals converge on the mitochondria, apoptosis is induced. Bcl-2 family members can be divided in two groups, according to their pro- or anti-apoptotic proteins. Their complex interaction kinetics determine if a cell will undergo apoptosis. One reason that accounts for the acquired apoptotic resistance of cancer cells is an increase of the anti-apoptotic or a decrease of the pro-apoptotic proteins.
Of great interest, specific blockers of anti-apoptotic proteins are currently available for use in patients. I propose to study the complex patterns of interaction of lung cancer three-dimensional cell cultures to understand how they attain additional apoptotic resistance. By these studies, I hope to identify the situations where the inhibition of anti-apoptotic proteins will be most effective and to find additional therapeutic targets that may be useful to improve current therapies available for lung cancer patients. The use of 3D models in studying multicellular resistance is novel and potentially important. We anticipate that these studies will not only clarify the role of mitochondria in acquire multi-cellular resistance but will also advance the use of spheroids as a more realistic model for studying tumor biology to uncover or to screen for other treatments. |