Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist
therapy.
Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of
cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to
therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-
essential amino acids in this complex scenario. Here we discuss the impact of
proline metabolism in
cancer development and progression, with particular emphasis on the
enzymes involved in
proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how
proline availability influences
collagen synthesis and maturation and the acquisition of
cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby
proline availability generates a cycle based on
collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and
tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic
cancers.