Adaptive Protein Translation by the Integrated Stress Response Maintains the Proliferative and Migratory Capacity of Lung Adenocarcinoma Cells.

The integrated stress response (ISR) is a conserved pathway that is activated by cells that are exposed to stress. In lung adenocarcinoma, activation of the ATF4 branch of the ISR by certain oncogenic mutations has been linked to the regulation of amino acid metabolism. In the present study, we provide evidence for ATF4 activation across multiple stages and molecular subtypes of human lung adenocarcinoma. In response to extracellular amino acid limitation, lung adenocarcinoma cells with diverse genotypes commonly induce ATF4 in an eIF2α-dependent manner, which can be blocked pharmacologically using an ISR inhibitor. Although suppressing eIF2α or ATF4 can trigger different biological consequences, adaptive cell-cycle progression and cell migration are particularly sensitive to inhibition of the ISR. These phenotypes require the ATF4 target gene asparagine synthetase (ASNS), which maintains protein translation independently of the mTOR/PI3K pathway. Moreover, NRF2 protein levels and oxidative stress can be modulated by the ISR downstream of ASNS. Finally, we demonstrate that ASNS controls the biosynthesis of select proteins, including the cell-cycle regulator cyclin B1, which are associated with poor lung adenocarcinoma patient outcome. Our findings uncover new regulatory layers of the ISR pathway and its control of proteostasis in lung cancer cells. IMPLICATIONS: We reveal novel regulatory mechanisms by which the ISR controls selective protein translation and is required for cell-cycle progression and migration of lung cancer cells.

HISTORICAL RESPONSE RATES OF SOMATOSTATIN ANALOGUES IN THE TREATMENT OF ACROMEGALY: A SYSTEMATIC REVIEW.

OBJECTIVE: In a completed phase III study (C2305, Clinicaltrials.gov identifier: NCT00600886), the reported rate of biochemical control with octreotide long-acting release (LAR) was lower than rates historically reported in patients pretreated and/or selected for response with somatostatin analogue (SSA) therapy. To assess whether lower efficacy rates of octreotide LAR in C2305 were influenced by study design, a systematic review of the literature was performed to evaluate response rates in previously published studies in acromegaly with similar design characteristics. METHODS: PubMed was used to search for English-language clinical studies of acromegaly published through May 2014. Prospective studies of medically naïve patients (≥20) treated with SSAs for ≤12 months that reported efficacy rates using composite endpoint measures (growth hormone [GH] and insulin-like growth factor 1 [IGF-1]) were included. Two separate authors independently screened abstracts and full-length articles of each study to determine eligibility. All authors met to review and reach consensus when primary reviewers disagreed on the inclusion or exclusion of specific studies. RESULTS: A total of 9 studies (N = 354 patients) were identified, with reported mean efficacy rates of 31% (range, 20-54%). Of note, reported mean efficacy rates were lower in studies enrolling patients naïve to any form of treatment (surgery, medical, and/or radiation) than in studies that enrolled only medically naïve patients. A limitation of this analysis was that inclusion criteria restricted the number of studies analyzed. CONCLUSION: Interpretation of biochemical response rates with SSAs is critically dependent on the context of the study and should be evaluated across clinical trials with similar study design characteristics.

Control of alveolar differentiation by the lineage transcription factors GATA6 and HOPX inhibits lung adenocarcinoma metastasis.

Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype.

Yin Yang 1 plays an essential role in breast cancer and negatively regulates p27.

Yin Yang 1 (YY1) is highly expressed in various types of cancers and regulates tumorigenesis through multiple pathways. In the present study, we evaluated YY1 expression levels in breast cancer cell lines, a breast cancer TMA, and two gene arrays. We observed that, compared with normal samples, YY1 is generally overexpressed in breast cancer cells and tissues. In functional studies, depletion of YY1 inhibited the clonogenicity, migration, invasion, and tumor formation of breast cancer cells, but did not affect the clonogenicity of nontumorigenic cells. Conversely, ectopically expressed YY1 enhanced the migration and invasion of nontumorigenic MCF-10A breast cells. In both a monolayer culture condition and a three-dimensional Matrigel system, silenced YY1 expression changed the architecture of breast cancer MCF-7 cells to that resembling MCF-10A cells, whereas ectopically expressed YY1 in MCF-10A cells had the opposite effect. Furthermore, we detected an inverse correlation between YY1 and p27 expression in both breast cancer cells and xenograft tumors with manipulated YY1 expression. Counteracting the changes in p27 expression attenuated the effects of YY1 alterations on these cells. In addition, YY1 promoted p27 ubiquitination and physically interacted with p27. In conclusion, our data suggest that YY1 is an oncogene and identify p27 as a new target of YY1.

Cell lineage specification in tumor progression and metastasis.

Cancer has long been compared to the aberrant development of human tissues. It was in the mid-19th century writings of Rudolf Virchow and Joseph Recamier that malignant tissue was first proposed to originate from embryonal cells. More contemporary perspectives on malignant progression are founded on the tenant that tumors emerge from somatic tissues. Yet examples linking the biological properties of cancer to developmental processes, both aberrant and normal, abound. In this review, we will discuss how the developmental lineage of tumor cells can influence the course of cancer metastasis. As new molecular mechanisms that control cell fate in various tissues are being rapidly uncovered, understanding how these well orchestrated programs can be subverted in human diseases should provide intriguing avenues for fundamental biological discoveries and new therapeutic opportunities in cancer.