Even if discovered at stage I and surgically removed, lung adenocarcinomas can relapse within months, spreading to lymph nodes, the contra-lateral lung, brain, bones, and the adrenal glands. The genetic determinants and molecular mechanisms involved in lung adenocarcinoma metastasis are obscure. During the previous grant period, the Massague group (RP1) began to clarify these issues. The work revealed a link between WNT and pulmonary tumor progression, identified a lung WNT gene signature (LWS) that predicts distant relapse in lung adenocarcinoma tumors ofany stage, provided tractable experimental models for bone and brain metastasis by lung adenocarcinoma cells, and uncovered H0XB9 as a WNT target gene that enhances tumor re-initiation in brain and bone marrow. Based on this progress.
Aims 1 and 2 RPl in this competing renewal will seek to identify genes and pathways that support the viability of lung adenocarcinoma micrometastases, with the goal of providing information to target such pathways in the adjuvant setting after resection in order to prevent metastasis.
Aim 3 in RP1 will build on this lab's recent progress in brain metastasis by focusing on the role of Serpins in this process, in particular Neuroserpin, a brain-specific member ofthis family of secreted protease inhibitors. RPI's preliminary data demonstrate that lung adenocarcinoma cells express Neuroserpin as a mediator of brain colonization, and that Neuroserpin is highly expressed in at least one-half of the human lung adenocarcinoma brain metastases that have so far been examined by immunohistochemistry. Other data from the Massague lab has recently shown that S100A8/9 are mediators of metastasis-linked chemoresistance in nfiouse models, and that S100A8 is amplified and highly expressed in human lung adenocarcinoma samples.
Aim 4 in RPl proposes to investigate the role of S100A8/9 in lung adenocarcinoma metastasis and response to chemotherapy, with the goal of uncovering new ways to augment the efficacy of targeted and conventional chemotherapies in lung cancers.

Public Health Relevance

Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This project addresses the two critical roadblocks to improving the care and curability of persons with lung adenocarcinomas: (1) understanding how adenocarcinomas spread to the brain (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Yu, Helena A; Arcila, Maria E; Harlan Fleischut, Megan et al. (2014) Germline EGFR T790M mutation found in multiple members of a familial cohort. J Thorac Oncol 9:554-8
Meador, Catherine B; Micheel, Christine M; Levy, Mia A et al. (2014) Beyond histology: translating tumor genotypes into clinically effective targeted therapies. Clin Cancer Res 20:2264-75
Valiente, Manuel; Obenauf, Anna C; Jin, Xin et al. (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156:1002-16
de Bruin, Elza C; Cowell, Catherine; Warne, Patricia H et al. (2014) Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov 4:606-19
Rekhtman, Natasha; Borsu, Laetitia; Reva, Boris et al. (2014) Unsuspected collision of synchronous lung adenocarcinomas: a potential cause of aberrant driver mutation profiles. J Thorac Oncol 9:e1-3
Yu, H A; Arcila, M E; Hellmann, M D et al. (2014) Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol 25:423-8
Lovly, Christine M; McDonald, Nerina T; Chen, Heidi et al. (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027-34
Yu, Helena A; Riely, Gregory J; Lovly, Christine M (2014) Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res 20:5898-907
Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling et al. (2014) Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep 7:999-1008
Haq, Rizwan; Fisher, David E; Widlund, Hans R (2014) Molecular pathways: BRAF induces bioenergetic adaptation by attenuating oxidative phosphorylation. Clin Cancer Res 20:2257-63

Showing the most recent 10 out of 59 publications