Thoracic malignancies account for the majority of cancer-related deaths. The most frequent lung cancer subtype is lung adenocarcinoma (LuAd), which displays remarkable biological heterogeneity and poor prognosis. A subset of LuAds rapidly diverge in their differentiation states, correlating with therapeutic resistance and metastatic relapse. Despite recent advances in cataloguing the genome of human lung cancers, the molecular and biological determinants of LuAd metastasis remain poorly understood. By employing innovative genomics and experimental approaches, we uncovered a molecular link between LuAd metastasis, airway epithelial specification, and metabolic reprogramming. In particular, we discovered a novel pathway that suppresses the metastatic proclivity of LuAd cells through the lineage transcription factor HOPX. HOPX not only directs alveolar differentiation, but also constrains a metabolic stress response by inhibiting the activity of the nutrient sensing kinase GCN2 (general control nonrepressed 2) and its downstream control of amino acid biosynthesis. We hypothesize that the suppression of HOPX primes high-grade LuAd cells to activate a metabolic pathway that pre-conditions them for subsequent metastasis. We refer to this pathway as a Lineage directed Adaptive Stress Response (LASR) and predict that it will increase the adaptive capacity of LuAd cells for various metastatic niches. Our hypothesis will be studied by integrating bioinformatics, molecular, metabolomic, and biological approaches.
In Aim 1, we will determine the transcriptional mechanism by which the LASR is activated in LuAds and ascertain its correlation with clinical outcome in human biospecimens.
In Aim 2, we will determine the function of key LASR enzymatic effectors in metastatic LuAd cells, by modeling conditions of metabolic and microenvironmental stress in circulation and the extracellular matrix. We will also perform a metabolic flux analysis of asparagine and serine, two amino acids whose catabolism is predicted to be required for LuAd cell dissemination and their emergence from dormancy.
In Aim 3, we will characterize the requirement for the LASR during LuAd differentiation, progression, and metastatic colonization in vivo. To this end, we will employ spatio-temporally controlled gain or loss of function approaches, using our established xenograft model of human LuAd as well as a novel targeting approach in a complementary genetically engineered mouse model. Our findings reveal how epithelial metabolic adaptation is under the direct control of developmental programs in the lungs. The deregulation of this novel pathway also provides a cogent mechanism for the elevated risk of certain early stage lung cancers to metastasize. Finally, our proposal will generate significant insight as to how prospective therapeutics directed against amino acid metabolism and proteostasis can be effectively harnessed for adjuvant therapy and/or the treatment of late stage metastasis.

Public Health Relevance

Thoracic malignancies are the principal source of cancer related deaths due to the rapid metastatic spread of lung cancer cells. Our novel multi-disciplinary approach proposes to reveal molecules that are specific to certain tissue cell types and which characterize this aggressive clinical course. We believe that this project will reveal fundamental new principles in pulmonary biology, cell metabolism, as well as provide more tailored therapeutic insight for lung cancer patients at risk of metastatic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA191489-03
Application #
9182876
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2014-12-15
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Arnal-Estapé, Anna; Nguyen, Don X (2015) Sweets for a bitter end: lung cancer cell-surface protein glycosylation mediates metastatic colonization. Cancer Discov 5:109-11
Cheung, W K C; Nguyen, D X (2015) Lineage factors and differentiation states in lung cancer progression. Oncogene 34:5771-80