Thyroid Transcription Factor‐1 modulation of secretome alters sensitivity to cisplatin in lung cancer

Abstract

Thyroid Transcription Factor‐1 (TTF‐1, alternatively known as NKX2‐1) is essential for lung development. Mice homozygous null for TTF‐1 fail to develop lungs and will die in utero. Like many developmental genes, TTF‐1 has also been shown to play a role in cancer development. Its role was originally elucidated when our lab and others showed that TTF‐1 resides in the 14q13.3 region that undergoes focal amplification in roughly 15% of lung adenocarcinomas, and knockdown of TTF‐1 retarded cell growth, suggesting a role as an oncogene. Since this finding, many tumor suppressive roles have been discovered, and TTF‐1 positivity in lung cancer is correlated with a better patient outcome. Our lab is interested in how TTF‐1 can alter lung cancer sensitivity to cisplatin, a common chemotherapy drug used in lung cancer. Our findings reveal that TTF‐1 can sensitize A549 cells to cisplatin. Furthermore, this sensitivity can be found in the secretome of TTF‐1 expressing cells, as conditioned media collected from TTF‐1 transfected cells can sensitize recipient cells to cisplatin relative to controls. We dissected the secretome between vesicle and soluble fractions. Exosomes failed to alter sensitivity to cisplatin. By probing the soluble secreted factors altered by TTF‐1 we found that GM‐CSF was the most differentially regulated. By adding a GM‐CSF neutralizing antibody to A549 cells expressing TTF‐1, we found a conferral of resistance to cisplatin. Conversely, by adding a recombinant GM‐CSF to A549 control cells not expressing TTF‐1, we found that it had the ability to confer sensitivity to cisplatin. Patient data from The Cancer Genome Atlas and the Director's Challenge Lung Study have found a strong positive correlation with TTF‐1 and GM‐CSF in patients. Intriguingly other chemotherapy drugs including carboplatin and gemcitabine did not show a differential effect with TTF‐1, suggesting that TTF‐1 may confer a special sensitivity to cisplatin and could serve as a guide for deciding patient treatment strategies.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.