Abstract | We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. |
Discussion | We have identified a set of orthogonal cell kinetics that include cell migration rate, proliferation potential, spontaneous cell death , and symmetric cancer stem cell division. |
Discussion | In a cancer stem cell-driven tumor, proliferation potential and spontaneous cell death have been shown to non-monotonically modulate overall tumor progression [16,30,31] while increased cell migration and symmetric CSC division always lead to accelerated tumor growth [27,35]. |
Methods | We explore orthogonal cell traits including cell migration to facilitate invasion [52] , spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations [53,54], symmetric cancer stem cell division that increases the cancer stem cell pool [55,56] , and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential [22,57]. |
Methods | Cell proliferation and migration are temporally mutually exclusive events, and cell death only occurs when cell actively attempts to proliferate. |
Proliferation potential determines cancer stem cell evolution and tumor growth | An increase in symmetric division probability ps and a decrease in cell death oz, and a later increase in cell migration follow the initial decrease in pmax. |
Proliferation potential determines cancer stem cell evolution and tumor growth | A weak but significant positive correlation is also observed with spontaneous cell death 0c (Fig. |
Proliferation potential determines cancer stem cell evolution and tumor growth | This lends support to previous theoretical observations that increased cell death counteracts cancer stem cell confinement [16,31] and promotes self-metastatic tumor eX |
Spatial phenotypic heterogeneity and implications for tumor biopsy | Proliferation potential and cell death distributions are skewed to the left approaching zero (Fig. |
Supporting Information | p5: probability of symmetric division; pmaxz proliferation potential; u: migration rate, oc: spontaneous cell death probability. |
Relating network connectivity to consensus drug mechanism | Consistently, a similar SAR trend was observed by evaluating each compound’s potency (EC50) in HeLa cells with regards to their ability to arrest cells in G2/M-phase and induce cell death . |
Relating network connectivity to consensus drug mechanism | This identified compound 8 (EC50.G2/M = 33 nM; EC50: cell death 2 60 nM) as the most potent compound in the series (810 Fig and $1 Text). |
Supporting Information | (B) For cell cycle arrest assays, cells were treated with compounds for 72 hours and the extent of cell death was quantified. |
Target validation of mitotic compounds from CSNAP predictions | This included defects in spindle assembly, chromosome segregation and cytokinesis that led to mitotic delay, post-mitotic defects (binuclear and polylobed nucleus) and apoptosis ( cell death ), suggesting that these targets were critical for cell division (S6 and S7 Figs) [62]. |