Cosimo Commisso's Research Focus
Research in the Commisso Lab is focused on biological discoveries that have the potential to lead to novel therapeutic strategies for cancer. Of particular interest to our laboratory are Ras-driven cancers, such as pancreatic cancer, which are extremely aggressive and are in urgent need of new and innovative therapies. The biological process that we study in the lab is called macropinocytosis, a fluid-phase form of bulk endocytic uptake, which we have linked to cancer cell metabolism in Ras-mutated tumors.
Cosimo Commisso's Research Report
Macropinocytosis is an endocytic mechanism of fluid-phase uptake that produces large intracellular vesicles known as macropinosomes. Macropinosomes are heterogeneous in size and shape and serve to internalize large volumes of extracellular fluid along with the associated membrane. In transformed cells, macropinocytosis is stimulated by oncogenes, such as Ras. Ras proteins are small, membrane-localized GTPases that are activated in response to growth factors and they regulate a variety of outputs, including cell proliferation, survival and invasion. Gain-of-function mutations in Ras-encoding genes cause Ras proteins to be trapped in their active state, leading to the constitutive activation of downstream pathways. The functional consequences of macropinocytosis stimulation in mutant Ras-expressing cells were unknown prior to our work. We have linked macropinocytic uptake in Ras-transformed cells to nutrient delivery and amino acid supply (Commisso et al., 2013). We demonstrated that the inhibition of this nutrient delivery pathway selectively compromises growth of Ras-driven tumors. With the long-term goal of specifically targeting such tumors, we have recently developed stream-lined methodology to detect and grade macropinocytosis in tumor tissue (Commisso et al., 2014). Our work was important for two main reasons. First, cancer cells are dependent on amino acids, such as glutamine, for their growth and survival. Therefore, the targeting of these amino acid supply pathways, such as macropinocytosis, represents a promising strategy in developing anti-cancer therapeutics. Second, macropinocytosis is emerging as a mechanism of entry for a variety of therapeutic agents, such as nanoparticles. Hence, identifying that this uptake pathway is active in Ras-driven tumors may have an impact on how these tumors are treated. The complete understanding of the functional significance of Ras-induced macropinocytosis to carcinogenesis and treatment ultimately depends on having a firm grasp of how this process is regulated and on the ability to specifically control it. To this end, a major research focus of the lab is to advance our understanding of the molecular pathways that drive macropinocytosis, which could lead to the identification of new molecular targets whose inhibition would restrain tumor growth and enhancers that could be manipulated to dial-up the uptake process in drug delivery strategies. Additional research interests in the lab include nutrient sensing pathways that are active in the context of macropinocytic uptake and macropinosome maturation, the process that leads to active protein catabolism within the tumor cell.
Cosimo Commisso's Bio
Dr. Commisso's doctoral studies were focused on various aspects of endocytosis pertaining to Notch signal transduction. Specifically, he analyzed the role of an endocytic protein known as Neuralized, which functions in the internalization of Notch ligands such as Delta and Jagged. As a doctoral trainee he gained extensive experience in cell biological and biochemical techniques pertaining to cellular trafficking. Subsequently, Dr. Commisso received postdoctoral training in pancreatic cancer at New York University School of Medicine. In that capacity he gained expertise in analyzing the complex signaling events mediated by oncogenic Ras during the initiation and progression of the disease. Additionally, he has expertise in the utilization of mouse models of pancreatic cancer including heterotopic/orthotopic xenografts, syngeneic heterotopic/orthotopic implantation and autochthonous models.
Commisso C, Flinn RJ, Bar-Sagi D
Nat Protoc 2014 Jan ;9(1):182-92
Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Grabocka E, Nofal M, Drebin JA, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, Bar-Sagi D
Nature 2013 May 30 ;497(7451):633-7
Functional analysis of the NHR2 domain indicates that oligomerization of Neuralized regulates ubiquitination and endocytosis of Delta during Notch signaling.
Liu S, Bonner JM, Chanet S, Commisso C, Skwarek LC, Schweisguth F, Boulianne GL
Mol Cell Biol 2012 Dec ;32(24):4933-45
Lee SW, Zhang Y, Jung M, Cruz N, Alas B, Commisso C
Dev Cell 2019 Aug 5 ;50(3):381-392.e5
Zhang Y, Commisso C
Trends Cancer 2019 Jun ;5(6):332-334
Philos Trans R Soc Lond B Biol Sci 2019 Feb 4 ;374(1765):20180153
Galenkamp KMO, Alas B, Commisso C
Methods Mol Biol 2019 ;1928:113-123
Lee SW, Alas B, Commisso C
Methods Mol Biol 2019 ;1882:171-181
Commisso C, Debnath J
Cancer Discov 2018 Jul ;8(7):800-802