{Reference Type}: Journal Article
{Title}: The glutathione S-transferase Gstt1 drives survival and dissemination in metastases.
{Author}: Ferrer CM;Cho HM;Boon R;Bernasocchi T;Wong LP;Cetinbas M;Haggerty ER;Mitsiades I;Wojtkiewicz GR;McLoughlin DE;Aboushousha R;Abdelhamid H;Kugel S;Rheinbay E;Sadreyev R;Juric D;Janssen-Heininger YMW;Mostoslavsky R;
{Journal}: Nat Cell Biol
{Volume}: 26
{Issue}: 6
{Year}: 2024 Jun 11
{Factor}: 28.213
{DOI}: 10.1038/s41556-024-01426-7
{Abstract}: Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.