title: Persistence to anti-cancer treatments in the stationary to proliferating transition.
abstract: The heterogeneous responses of clonal cancer cells to treatment is understood to be caused by several factors, including stochasticity, cell-cycle dynamics, and different micro-environments. In a tumor, cancer cells may encounter fluctuating conditions and transit from a stationary culture to a proliferating state, for example this may occur following treatment. Here, we undertake a quantitative evaluation of the response of single cancerous lymphoblasts (L1210 cells) to various treatments administered during this transition. Additionally, we developed an experimental system, a "Mammalian Mother Machine," that tracks the fate of thousands of mammalian cells over several generations under transient exposure to chemotherapeutic drugs. Using our developed system, we were able to follow the same cell under repeated treatments and continuously track many generations. We found that the dynamics of the transition between stationary and proliferative states are highly variable and affect the response to drug treatment. Using cell-cycle markers, we were able to isolate a subpopulation of persister cells with distinctly higher than average survival probability. The higher survival rate encountered with cell-cycle phase specific drugs was associated with a significantly longer time-till-division, and was reduced by a non cell-cycle specific drug. Our results suggest that the variability of transition times from the stationary to the proliferating state may be an obstacle hampering the effectiveness of drugs and should be taken into account when designing treatment regimens.
authors: a Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University , Jerusalem , Israel.|b Department of Microbiology and Molecular Genetics , IMRIC, The Hebrew University Hadassah Medical School , Jerusalem , Israel.
authors: Sivan
authors: S
authors: Pearl Mizrahi
authors: a Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University , Jerusalem , Israel.
authors: Orit
authors: O
authors: Gefen
authors: b Department of Microbiology and Molecular Genetics , IMRIC, The Hebrew University Hadassah Medical School , Jerusalem , Israel.
authors: Itamar
authors: I
authors: Simon
authors: a Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University , Jerusalem , Israel.
authors: Nathalie Q
authors: NQ
authors: Balaban
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005453:Fluorescence; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D025801:Ubiquitin; D003561:Cytarabine
keywords: cell-cycle; chemotherapy; microfluidics; persistence; proliferating; quiescence; stationary