Role of mutant p53 as mechanosensitive regulator of amino-acid metabolism in breast cancer

Amino acids are crucial nutrients for cancer cells since they provide plenty of metabolic and energetic intermediates and promote their survival in challenging environments, thus enabling them to proliferate, disseminate and generate metastases. Tumors are indeed avid for amino acids and, consequently, they aberrantly increase amino acids intake, biosynthesis and catabolism. This metabolic reprogramming represents an Achille’s heel of tumors. Thus, unveiling the oncogenic drivers that reprogram amino acid metabolism in cancer is fundamental to understand disease progression and to find therapeutic opportunities. In this work, we disclosed a new role of mutp53 in regulating amino acid metabolism in breast cancer cells. We demonstrated that mutp53 promotes synthesis of aspartate, serine and glycine through upregulation of amino acids biosynthetic enzymes and increases the expression of specific amino acids transporters. Our findings indicate that mutp53, unleashing this metabolic program, supports metabolic adaptation to environmental stresses, such as nutrient starvation. Indeed, in conditions of amino acids scarcity, mutp53 sustained cancer cells survival and proliferation via upregulation of serine synthesis and BCAAs/bulky amino acids intake. Furthermore, we showed that a stiff ECM cooperates with mutp53 in the induction of such genes, unveiling a novel branch of amino acid metabolism regulated in response to mechanical inputs and fostered by mutp53. Notably, inhibition of either mechanotransduction or serine synthesis or BCAAs/bulky amino acids intake was able to blunt the pro-survival effects exerted by mutp53 on cancer cells proliferation in amino acids deprivation.

Amino acids are crucial nutrients for cancer cells since they provide plenty of metabolic and energetic intermediates and promote their survival in challenging environments, thus enabling them to proliferate, disseminate and generate metastases. Tumors are indeed avid for amino acids and, consequently, they aberrantly increase amino acids intake, biosynthesis and catabolism. This metabolic reprogramming represents an Achille’s heel of tumors. Thus, unveiling the oncogenic drivers that reprogram amino acid metabolism in cancer is fundamental to understand disease progression and to find therapeutic opportunities. In this work, we disclosed a new role of mutp53 in regulating amino acid metabolism in breast cancer cells. We demonstrated that mutp53 promotes synthesis of aspartate, serine and glycine through upregulation of amino acids biosynthetic enzymes and increases the expression of specific amino acids transporters. Our findings indicate that mutp53, unleashing this metabolic program, supports metabolic adaptation to environmental stresses, such as nutrient starvation. Indeed, in conditions of amino acids scarcity, mutp53 sustained cancer cells survival and proliferation via upregulation of serine synthesis and BCAAs/bulky amino acids intake. Furthermore, we showed that a stiff ECM cooperates with mutp53 in the induction of such genes, unveiling a novel branch of amino acid metabolism regulated in response to mechanical inputs and fostered by mutp53. Notably, inhibition of either mechanotransduction or serine synthesis or BCAAs/bulky amino acids intake was able to blunt the pro-survival effects exerted by mutp53 on cancer cells proliferation in amino acids deprivation.