ATF4 and familial pancreatic carcinoma: Our findings are supported by the following previous studies: (1) the SPHK1 /S1P signaling promotes EMT in breast cancer and colon cancer [32, 39]; (2) EMT cells constitutively activate the PERK–eIF2α–ATF4 signaling for them to invade/metastasize and form tumor-spheres [31], (3) knockdown of SPHK1 inhibits the phosphorylation of IRE1α and PERK, reduces ATF4 expression and ATF6 activation, alleviates ER stress in mice [16], and 4) expression of the EMT transcription factor Snail2 is depended on ATF4 production in the process of EMT caused by glutamine deficiency in pancreatic cancer [40].