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K. Sutherland
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MS02 - Stem Cells and Epigenetics in Lung Cancer (ID 19)
- Event: WCLC 2013
- Type: Mini Symposia
- Track: Biology
- Presentations: 1
- Moderators:G. Sozzi, J. Minna
- Coordinates: 10/28/2013, 14:00 - 15:30, Bayside 103, Level 1
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MS02.1 - Stem Cells & the Cell of Origin of Lung Cancer (ID 462)
14:05 - 14:25 | Author(s): K. Sutherland
- Abstract
- Presentation
Abstract
The cellular hierarchy of the lung is quite complex and it is believed that different progenitor cells and stem cell populations residing within distinct spatial regions of the lung are responsible for orchestrating lung development, regeneration and repair. These different stem cell populations are also likely to be instrumental in the development of the various cancers in lung as particular lung tumour subtypes are almost exclusively found in distinct compartments within the lung. Squamous cell carcinomas are thought to arise from the proximal airways, small cell lung cancer are predominantly located in the bronchioles while adenocarcinomas are more frequently detected the in the distal part of the lung. To investigate the cellular origin of lung cancer, we utilized Cre-loxP recombination technology, which is an effective method for expressing or deleting a target gene in Cre-expressing cells. We generated a series of recombinant adenoviruses expressing Cre recombinase from specific lung epithelial gene promoters. For these studies we chose to target Clara cells, alveolar type 2 (AT2) cells and neuroendocrine (NE) cells. Comprehensive experiments performed in Rosa26R-lacZ and mT/mG reporter animals showed that these viruses exhibit a high level of cell selectivity in the adult mouse lung. To address the cellular origins of small cell lung cancer (SCLC) we have utilised a sporadic mouse model of small cell lung cancer based on the conditional inactivation of the tumour suppressor genes Tp53 and Rb1. We infected Tp53F/F;Rb1F/F animals with our cell type-restricted Adeno-Cre viruses: Ad5-CC10-Cre, Ad5-SPC-Cre and Ad5-CGRP-Cre. Results from these studies show that inactivation of Trp53 and Rb1 can efficiently transform neuroendocrine (CGRP-positive) and to a lesser extent, alveolar type 2 (SPC-positive) cells leading to SCLC. In contrast, CC10-expressing cells were largely resistant to transformation. The results clearly indicate that neuroendocrine cells serve as the predominant cell-of-origin of SCLC in this model. Interestingly a different, cell type specificity was observed when a K-rasG12D oncogene-driven non-small cell lung cancer (NSCLC) model was used to reveal the cell of origin of NSCLC (mostly of adenomas and adenocarcinomas). In this case we noted a difference between K-rasLSL-G12D/+ and K-rasLSL-G12D/+;Trp53F/F animals following infection with our cell type-restricted adenoviruses. In K-rasLSL-G12D/+ mice alveolar type 2 cells appeared to be the most effective target cell for inducing adenomas, whereas in K-rasLSL-G12D/+;Trp53F/F mice multiple cell types had the capacity to give rise to adenomas and adenocarcinomas. Moreover, preliminary data from these experiments indicates that the cell-of-origin may also influence the characteristics and behaviour of the resulting tumours. Taken together, our data show that both cell specific features and the nature of the genetic lesion(s) are critical factors in determining the tumour initiating capacity of lung (progenitor) cells to give rise to various lung cancer subtypes.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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O12 - Lung Cancer Biology II (ID 87)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:Y. Nakanishi, B. Solomon
- Coordinates: 10/29/2013, 10:30 - 12:00, Parkside 110 A+B, Level 1
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O12.04 - DISCUSSANT (ID 3896)
11:00 - 11:15 | Author(s): K. Sutherland
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
