Calcium channel α2δ1 subunit is a functional marker and therapeutic target for tumor-initiating cells in non-small cell lung cancer

It is hypothesized that tumor-initiating cells (TICs) with stem cell-like properties constitute a sustaining force to drive tumor growth and renew fully established malignancy. However, the identification of such a population in non-small cell lung carcinoma (NSCLC) has been hindered by the lacking of reliable surface markers, and very few of the currently available surface markers are of functional significance. Here, we demonstrate that a subpopulation of TICs could be specifically defined by the voltage-gated calcium channel alpha 2 delta 1 subunit from non-small cell lung carcinoma (NSCLC) cell lines and clinical specimens. The alpha 2 delta 1(+) NSCLC TICs are refractory to conventional chemotherapy, and own stem cell-like properties such as self-renewal, and the ability to generate heterogeneous tumors in NOD/SCID mice. Moreover, alpha 2 delta 1(+) NSCLC cells are more enriched for TICs than CD133(+), or CD166(+) cells. Interestingly, alpha 2 delta 1 is functionally sufficient and indispensable to promote TIC properties by mediating Ca2+ influx into cells, which subsequently activate Calcineurin/NFATc2 signaling that directly activates the expression of NOTCH3, ABCG2. Importantly, a specific antibody against alpha 2 delta 1 has remarkably therapeutic effects on NSCLC xenografts by eradicating TICs. Hence, targeting alpha 2 delta 1 to prevent calcium influx provides a novel strategy for targeted therapy against TICs of NSCLC.