Macropinocytosis: A Ras-driven Metabolic Adaptation

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 Path Forward...

 

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.

All images captured and processed by C. Commisso

 

 

All images captured and processed by C. Commisso

 

 

© 2019 by Cosimo Commisso

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