Overshoot during phenotypic switching of cancer cell populations.
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.
Center for Complexity and Biosystems, Department of Physics, University of Milano, via Celoria 16, 20133 Milano, Italy.|CNR - Consiglio Nazionale delle Ricerche, Istituto per l'Energetica e le Interfasi, Via R. Cozzi 53, 20125 Milano, Italy.
Alessandro L
AL
Sellerio
Istituto Neurologico Carlo Besta, Milano, Italy.
Emilio
E
Ciusani
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
Noa Bossel
NB
Ben-Moshe
Dipartimento di Scienze Bomediche per la Salute, University of Milano, Milano, Italy.
Stefania
S
Coco
Dipartimento di Scienze Bomediche per la Salute, University of Milano, Milano, Italy.
Andrea
A
Piccinini
Laboratory of Atomic and Solid State Physics, Physics Department, Cornell University, Ithaca, NY.|Institute of Biotechnology, Cornell University, Ithaca, NY.
Christopher R
CR
Myers
Laboratory of Atomic and Solid State Physics, Physics Department, Cornell University, Ithaca, NY.
James P
JP
Sethna
Center for Complexity and Biosystems, Department of Bioscience, University of Milano, via Celoria 26, 20133 Milano, Italy.
Costanza
C
Giampietro
Center for Complexity and Biosystems, Department of Physics, University of Milano, via Celoria 16, 20133 Milano, Italy.|CNR - Consiglio Nazionale delle Ricerche, Istituto per l'Energetica e le Interfasi, Via R. Cozzi 53, 20125 Milano, Italy.|ISI Foundation, Via Alassio 11C, Torino, Italy.|Department of Applied Physics, Aalto University, P.O. Box 14100, FIN-00076, Aalto, Finland.
Stefano
S
Zapperi
Center for Complexity and Biosystems, Department of Bioscience, University of Milano, via Celoria 26, 20133 Milano, Italy.
Caterina A M
CAM
La Porta
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010641:Phenotype; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C106330:CXCR6 protein, human; C484065:NGFR protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D017475:Receptors, Nerve Growth Factor; D011991:Receptors, Virus