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- Title
Defining rules for cancer cell proliferation in TRAIL stimulation.
- Authors
Deveaux, William; Hayashi, Kentaro; Selvarajoo, Kumar
- Abstract
Owing to their self-organizing evolutionary plasticity, cancers remain evasive to modern treatment strategies. Previously, for sensitizing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant human fibrosarcoma (HT1080), we developed and validated a dynamic computational model that showed the inhibition of protein kinase (PK)C, using bisindolylmaleimide (BIS) I, enhances apoptosis with 95% cell death. Although promising, the long-term effect of remaining ~ 5% cells is a mystery. Will they remain unchanged or are they able to proliferate? To address this question, here we adopted a discrete spatiotemporal cellular automata model utilizing simple rules modified from the famous "Conway's game of life". Based on three experimental initializations: cell numbers obtained from untreated (high), treatment with TRAIL only (moderate), and treatment with TRAIL and BIS I (low), the simulations show cell proliferation in time and space. Notably, when all cells are fixed in their initial space, the proliferation is rapid for high and moderate cell numbers, however, slow and steady for low number of cells. However, when mesenchymal-like random movement was introduced, the proliferation becomes significant even for low cell numbers. Experimental verification showed high proportion of mesenchymal cells in TRAIL and BIS I treatment compared with untreated or TRAIL only treatment. In agreement with the model with cell movement, we observed rapid proliferation of the remnant cells in TRAIL and BIS I treatment over time. Hence, our work highlights the importance of mesenchymal-like cellular movement for cancer proliferation. Nevertheless, re-treatment of TRAIL and BIS I on proliferating cancers is still largely effective. Author summary: Cancers are evasive to even the most modern state-of-the-art treatment strategies. Although numerous studies, on distinct drug treatments, have shown large portions reaching cell death, the long-term effect of the remaining resistant cells is a mystery. Will they remain unchanged or are they able to proliferate? To address this question, an international team from Japan, France, and Singapore, led by Kumar Selvarajoo, has developed a spatiotemporal cellular automata model that tracks cancer proliferation in time and space, for cancers untreated and treated with potential drug targets (TRAIL and TRAIL plus BIS). Their model, based on setting rules for cancer proliferation, predicted that mesenchymal-like cellular movement, rather than actual cancer numbers or size, is key for cancer proliferation. The results were subsequently validated experimentally on human fibrosarcoma.
- Subjects
CELL proliferation; PROTEIN kinases; CELL death; FIBROSARCOMA; CANCER treatment
- Publication
NPJ Systems Biology & Applications, 2019, Vol 5, Issue 1, pN.PAG
- ISSN
2056-7189
- Publication type
Article
- DOI
10.1038/s41540-019-0084-5