Characterization of lung cancer stem cells
Our aim is to delineate the molecular drivers of resistance to radio- and chemotherapy to allow for identification of novel treatment regimen and biomarkers in lung cancer.
Tumor initiating cells (TICs) or cancer stem cells (CSC) are suggested to have an increased capacity to survive treatment and to be responsible for resistance to chemo- and radiotherapy (CT and RT). By defining the specific targets and pathways that are deregulated in TICs we wish to improve our understanding of tumor response to treatment. We are applying both global and more focused methods for analysis of DNA damage signaling in TICs at the transcriptional, genomic, phosphoproteomic and epigenetic level. Additionally, we are screening substances with possible potency in TICs. We have access to patient material to validate our findings.
We recently linked the CD133+ CSC-like proportion of non-small cell lung carcinoma (NSCLC) cells to increased cell survival, decreased apoptotic signaling as well as an altered cell cycle distribution upon CT/RT treatment as compared to bulk cells of the same cell line. We confirmed a cisplatin-refractory phenotype of NSCLC TICs in vivo in a mouse xenograft model, and we showed that altered DNA repair signaling is one possible factor contributing to therapy resistance, which may be exploited for DNA damage-sensitizing purposes.
Resistance to DNA-damaging treatment in non-small cell lung cancer tumor-initiating cells involves reduced DNA-PK/ATM activation and diminished cell cycle arrest.
Lundholm L, Hååg P, Zong D, Juntti T, Mörk B, Lewensohn R, et al
Cell Death Dis 2013 Jan;4():e478