Figure 12. Autophagy and two-compartment tumor metabolism: Defining the roles of DRAM, LKB1, and GOLPH3. DRAM and LKB1 activate AMP-kinase in cancer-associated fibroblasts, driving autophagy, mitophagy, and mitochondrial dysfunction. Conversely, GOLPH3 expression in cancer cells mediates autophagy resistance, likely via the induction of mitochondrial biogenesis, or the enhancement of mitochondrial function. Thus, compartment-specific regulation of autophagy results in a “parasitic” form of stromal-epithelial metabolic coupling. HQ, hydroxy-chloroquine; RA, Rapamycin analogs. Both chloroquine and rapamycin analogs could functionally disrupt metabolic coupling, by simultaneously turning “on” or “off” autophagy in both cellular compartments (cancer cells and stromal fibroblasts). CAFs, cancer-associated fibroblasts.