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FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas.

ABSTRACT: Lung cancer remains one of the most prominent public health challenges, accounting for the highest incidence and mortality among all human cancers. While pulmonary invasive mucinous adenocarcinoma (PIMA) is one of the most aggressive types of non-small cell lung cancer, transcriptional drivers of PIMA remain poorly understood. In the present study, we found that Forkhead box M1 transcription factor (FOXM1) is highly expressed in human PIMAs and associated with increased extracellular mucin deposition and the loss of NKX2.1. To examine consequences of FOXM1 expression in tumor cells in vivo, we employed an inducible, transgenic mouse model to express an activated FOXM1 transcript in urethane-induced benign lung adenomas. FOXM1 accelerated tumor growth, induced progression from benign adenomas to invasive, metastatic adenocarcinomas, and induced SOX2, a marker of poorly differentiated tumor cells. Adenocarcinomas in FOXM1 transgenic mice expressed increased MUC5B and MUC5AC, and reduced NKX2.1, which are characteristics of mucinous adenocarcinomas. Expression of FOXM1 in KrasG12D transgenic mice increased the mucinous phenotype in KrasG12D-driven lung tumors. Anterior Gradient 2 (AGR2), an oncogene critical for intracellular processing and packaging of mucins, was increased in mouse and human PIMAs and was associated with FOXM1. FOXM1 directly bound to and transcriptionally activated human AGR2 gene promoter via the -257/-247 bp region. Finally, using orthotopic xenografts we demonstrated that inhibition of either FOXM1 or AGR2 in human PIMAs inhibited mucinous characteristics, and reduced tumor growth and invasion. Altogether, FOXM1 is necessary and sufficient to induce mucinous phenotypes in lung tumor cells in vivo.

SUBMITTER: Milewski D

PROVIDER: S-EPMC5755924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIntraoperative molecular imaging (IMI) with folate-targeted NIR tracers has been shown to improve lesion localization in more than 80% of lung adenocarcinomas. However, mucinous adenocarcinomas (MAs) and invasive mucinous adenocarcinomas (IMAs) of the lung, which are variants of adenocarcinoma, appear to have decreased fluorescence despite appropriate folate receptor expression on the tumor surface. We hypothesized that the etiology may be related to light excitation and emission through non-Newtonian fluid (mucin) produced by goblet and columnar cancer cells.MethodsIntraoperative data for 311 subjects were retrospectively reviewed from a prospectively collected 6-year database. For standardization, all patients underwent infusion of the same targeted molecular optical contrast agent (pafolacianine, folate receptor-targeted NIR fluorochrome) for lung cancer resections. Then, the ratio of the mean fluorescence intensity of the tumors and background tissues (TBR) was calculated. Tumors were examined for mucin, FRa, FRb, and immunofluorescent tracer uptake by a board-certified pathologist. The optical properties of mucin analyzed by imaging software were used to create in vitro gel models to explore the effects on NIR tracer fluorescence intensity.ResultsA large proportion (192, 62%) of the patients were female, with an average of 62.8 years and a 34-year mean pack smoking history. There were no severe (Clavien-Dindo > III) complications related to pafolacianine infusion. A total of 195 lesions in the study were adenocarcinomas, of which 19 (6.1%) were of the mucinous subtype. A total of 14/19 of the patients had a smoking history, and more than 74% of the IMA lesions were in the lower lobes. IMA lesions had a lower in situ TBR than nonmucinous adenocarcinomas (2.64 SD 0.23) vs (3.45 SD 0.11), respectively (p < 0.05). Only 9/19 (47%) were localized in situ. Tumor bisection and removal of mucin from IMAs significantly increased pafolacianine fluorescence, with resultant TBR not being significantly different from the control group (4.67 vs 4.89) (p = 0.19). Of the 16 lesions that underwent FR expression analysis, 15/16 had FR presence on cancer cells or tumor-associated macrophages in the tumor microenvironment. There was no statistically significant difference in fluorescence intensity during immunofluorescence analysis (4.99 vs 5.08) (p = 0.16). Physical removal of mucin from IMAs improved the TBR from 3.11 to 4.67 (p < 0.05). In vitro analysis of the impact of synthetic non-Newtonian fluid (agarose 0.5%) on NIR tracer fluorescence showed a decrease in MFI by a factor of 0.25 regardless of the concentration for each 5 mm thickness of mucin.ConclusionThe mucinous subtype of lung adenocarcinomas presents a unique challenge in pafolacianine-targeted IMI-guided resections. The presence of non-Newtonian fluids presents a physical barrier that dampens the excitation of the tracer and fluorescence emission detected by the camera. Knowledge of this phenomenon can allow the surgeon to critically analyze lesion fluorescence parameters during IMI-guided lung cancer resections.

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FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas.

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