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Thus, acidosis is not merely a byproduct of altered metabolism in tumors. Rather, it is a dominant factor in the tumor microenvironment that orchestrates a boost in mitochondrial energy production, thereby rendering cancer cells resilient to different types of stress.

Acidosis induces mitochondrial fusion by preventing oncogene-induced mitochondrial fragmentation. Strikingly, acidosis triggers this effect by inactivating cytoplasmic ERK1/2 and, in turn, the mitochondrial fission factor DRP1, revealing a direct link between oncogenic Ras and bioenergetics.

…and goes along with increased mitochondrial activity and a switch from glycolysis to oxidative mitochondrial metabolism, leading to a boost in ATP production that renders cancer cells resilient to diverse stresses.

Acidosis triggers profound changes in the shape and architecture of mitochondria, which reorganize from fragmented organelles into fused tubular networks. Mitochondrial fusion is required for cell proliferation and survival under acidosis…

In subsequent stress combination screens and follow-up studies, we find that acidosis overwrites the effects of many other stresses such as shortages in nutrients or growth factors. For example, merely lowering the media pH enables glucose-starved cancer cells to re-enter proliferation!

Through genome-wide CRISPR screens, we characterized fitness genes under diverse metabolic stresses and sequentially screened 771 stress-specific fitness genes in pancreatic tumors in vivo. Gene dependency profiles in vivo closely mimicked only one stress condition in cell culture: Acidosis!