Stem Cells in Lung Cancer
Stem Cells in Lung Cancer
New Faculty II
Stem Cell Use:
Adult Stem Cell
Cancer Stem Cell
Statement of Benefit to California:
Year 1We identified a putative tumor-initiating stem/progenitor cell that goes rise to smoking-associated non small cell lung cancer (NSCLC). We examined 399 NSCLC samples for this tumor-initiating stem/progenitor cell and found that the presence of this cell in the tumor gave rise to a significantly worse prognosis and was associated with metastatic disease. This stem/progenitor cell is known to be important for repair of the airway and is present in precancerous lesions. We believe that this cell undergoes aberrant repair after smoking injury, which leads to lung cancer. We are currently trying to identify the genetic and epigenetic mechanisms involved in this aberrant repair as a means to identify a novel therapy to prevent the development of lung cancer. The presence of these stem/progenitor cells may also be used as a biomarker of poor prognostic NSCLC even in early stage disease. We have identified markers on these stem/progenitor tumor-initiating cells and identified sub-populations of these cells. We are now determining the stem cell capabilities of each of these sub-populations. We are using a model of the development of lung cancer to determine if giving a stem/progenitor cell sub-population for repair can prevent NSCLC from developing. We examined the blood of patients diagnosed with a lung nodule for circulating epithelial stem/progenitor cells. We found that the presence of these cells in the blood of patients predicted the presence of a subtype of NSCLC as compared to a benign lung nodule. We are currently obtaining many more blood samples from patients to further determine whether circulating epithelial stem/progenitor cells could be used as a biomarker of early NSCLC.
Year 2We have found a stem cell that is important for lung repair after injury that is located in a protected niche in the airway. After repeated injury, for example in smokers, these stem cells persist in an abnormal location on the surface of the airway and replicate and form precancerous areas in the lung. The presence of these stem cells in lung cancer tumors was associated with a poor prognosis with an increased chance of relapse and metastasis.This was especially true in current and former smokers. We therefore believe we have found a putative stem cell that is a tumor initiating cell for lung cancer. We developed a method to isolate these lung stem cells and to profile these cells and developed in vitro and in vivo models to assess their stem cell properties. Finally, we examined human blood samples to assess levels of surrogate markers of these stem cells to assess whether we could use this as a biomarker to predict the presence or absence of lung cancer in patients with a lung nodule.
Year 3We found a stem cell that is important for lung repair after injury that we believe may form precancerous areas in the lung. We are characterizing these stem cells and identifying pathways involved in normal repair and aberrant repair that leads to lung cancer. We are also isolating this stem cell population and other cell populations from the airway and inducing genetic changes to determine the tumor initiating cell/s for lung cancer. We are also examining the effect the environment may have on the regulation of genes in these stem cells, in precancerous areas and in lung cancers. Finally, we are examining human blood samples to assess levels of surrogate markers of these stem cells to assess whether we could use this as a biomarker to predict the presence or absence of lung cancer in patients with a lung nodule.
Year 4During this period of funding we discovered a method to reproducibly recover stem cells from human airways and grow them in a dish into mature airway cells. We also discovered the role that certain metabolic cell processes play in regulating the repair after airway injury. We believe that an inability to shut off these processes leads to abnormal repair and lung cancer and are actively investigating this. We are also determining whether the stem cells we isolate from the airways are the stem cells for lung cancer and how they might give rise to lung cancer.
Year 5In the last year of funding we identified a novel mechanism that tightly controls airway stem cell proliferation for repair after injury. We found that perturbing this pathway results in precancerous lesions that can ultimately lead to lung cancer. Correcting the abnormalities in this pathway that are seen in smokers could allow the development of targeted chemoprevention strategies to prevent the development of precancerous lesions and therefore lung cancer in at risk populations. We also continued our work on trying to identify a cell of origin for squamous lung cancer and identifying the critical drive mutations that are required for squamous lung cancer to develop.
- Stem Cells Transl Med (2012) Isolation and in vitro characterization of Basal and submucosal gland duct stem/progenitor cells from human proximal airways. (PubMed: 23197663)
- J Vis Exp (2012) Isolation of Basal cells and submucosal gland duct cells from mouse trachea. (PubMed: 23007468)
- Respirology (2012) Repair and regeneration of tracheal surface epithelium and submucosal glands in a mouse model of hypoxic-ischemic injury. (PubMed: 22617027)
- Semin Respir Crit Care Med (2011) Evolving concepts in lung carcinogenesis. (PubMed: 21500122)
- Stem Cells (2011) A Novel Stem/Progenitor Cell Population from Murine Tracheal Submucosal Gland Ducts with Multipotent Regenerative Potential. (PubMed: 21710468)
- Cancer Res (2010) Presence of a putative tumor-initiating progenitor cell population predicts poor prognosis in smokers with non-small cell lung cancer. (PubMed: 20710044)