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Macropinocytosis fuels cancer cell growth and drug resistance


To support their accelerated non-homeostatic proliferation, cancer cells depends on access to extracellular nutrients derived from the tumor vasculature. However, dysfunctional tumor vasculature and high interstitial pressure limit tumor perfusion leaving many tumor cells nutrient-deprived. To bypass this nutrient limitation, RAS driven cancer cells recycle their own nutrients via autophagy or scavenge macromolecules from the tumor microenvironment (TME) via macropinocytosis. Oncogenic mutations in RAS promote macropinocytosis, a bulk scavenging process through which components in the TME can be non-specifically acquired. When macropinosomes fuse with lysosomes, degradative enzymes release nutrients that can support cancer cell growth and proliferation. We report macropinocytosis is not just a RAS driven phenotype but a cancer phenotype. Lipid PIP3 generated by the PI3K pathway is necessary for closure of macropinosomes in most contexts. We identified prostate and breast cancers with hyper-activation of the PI3K pathway perform macropinocytosis in an AMPK dependent manner. AMPK mediated macropinocytosis is necessary for proliferation of PTEN-deficient cells in low nutrients but not autophagy. Because scavenging allows cells to acquire nutrients from cell extrinsic sources, it is likely to play a greater role in promoting tumor growth than cell-autonomous autophagy, which leads to atrophy. Necrosis is observed in most solid tumors; necrotic cell debris is selectively scavenged via macropinocytosis. Nutrient-deprived macropinocytic breast cancer cells acquired not just amino acids, but also sugars, lipids, and nucleotides from necrotic cell debris (necrocytosis) suggesting macropinocytosis plays a larger role than previously appreciated in supporting cancer anabolism. In addition, necrocytosis also conferred resistance to various therapies that target de novo nucleotide synthesis, fatty acid synthesis as well standard of care genotoxic therapies resulting in the first demonstration that scavenging confers drug resistance. Together, these studies suggest that macropinocytosis inhibitors could have therapeutic value in many cancer patients, particularly in combination with conventional therapies.

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