The dynamics of tumor cell populations is hotly debated: do populations derive hierarchically from a subpopulation of cancer stem cells (CSCs), or are stochastic transitions that mutate differentiated cancer cells to CSCs important? Here we argue that regulation must also be important. We sort human melanoma cells using three distinct cancer stem cell (CSC) markers - CXCR6, CD271 and ABCG2 - and observe that the fraction of non-CSC-marked cells first overshoots to a higher level and then returns to the level of unsorted cells. This clearly indicates that the CSC population is homeostatically regulated. Combining experimental measurements with theoretical modeling and numerical simulations, we show that the population dynamics of cancer cells is associated with a complex miRNA network regulating the Wnt and PI3K pathways. Hence phenotypic switching is not stochastic, but is tightly regulated by the balance between positive and negative cells in the population. Reducing the fraction of CSCs below a threshold triggers massive phenotypic switching, suggesting that a therapeutic strategy based on CSC eradication is unlikely to succeed.
Overshoot during phenotypic switching of cancer cell populations / A.L. Sellerio, E. Ciusani, N.B. Ben-Moshe, S. Coco, A. Piccinini, C.R. Myers, J.P. Sethna, C. Giampietro, S. Zapperi, C.A.M. La Porta. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 5(2015 Oct), pp. 15464.1-15464.14.
|Titolo:||Overshoot during phenotypic switching of cancer cell populations|
ZAPPERI, STEFANO (Penultimo)
LA PORTA, CATERINA (Ultimo)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore FIS/02 - Fisica Teorica, Modelli e Metodi Matematici
Settore MED/43 - Medicina Legale
|Data di pubblicazione:||ott-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/srep15464|
|Appare nelle tipologie:||01 - Articolo su periodico|