Understanding the interplay of Darwinian evolution and Lamarkian induction in drug resistance
MOLAB
Thursday June 27, 2019
Mathematical Oncology Laboratory

A group of MOLAB researchers, together with coworkers from Institute for Biological Research "Sinisa Satankovic" at the University of Belgrade (Serbia), have developed and validated a mathematical model for describing the dynamics displayed by a system of non-small-cell lung carcinoma cells which exhibit a complex interplay between Darwinian selection, Lamarckian induction and transfer of extracellular microvesicle under the action of chemotherapy.

Drug resistance in cancer has major implications for patients' outcome. It is related to processes involved in the decrease of drug efficacy, which are strongly influenced by intratumor heterogeneity and changes in the microenvironment. Heterogeneity arises, to a large extent, from genetic mutations analogously to Darwinian selection, but can also emerge as a consequence of epigenetic mutations driven by stochastic events. An important exogenous source of alterations is the action of chemotherapeutic agents, which not only affects the signalling pathways but also the interactions among cells. 

In the study researchers provided experimental evidence from in vitro assays and put forward a mathematical kinetic transport model consisting of an unified theoretical framework encompassing Darwinian selection, Lamarkian induction and the transfer of extracellular microvesicles by tumor cells carrying P-glycoprotein, which is a membrane transporter capable to efflux large panels of structurally and functionally unrelated drugs. The mathematical model explained the experimental results and revealed a number of intriguing cancer cell dynamics such as that, under exogenous stress conditions, sensitive tumor cells are more likely to accept extracellular microvesicles shed by resistant tumor cells carrying P-glycoprotein. This preferential uptake of microvesicles by sensitive tumor cells opens new potential therapeutic routes to deal with multi-drug-resistance in cancer. The mathematical model was used to study different therapeutic protocols highlighting the importance of  administration timings , and the high variability in response as a consequence of Lamarkian induction and microvesicle transfer, which could range from tumor control to treatment failure.

Álvarez-Arenas A, Podolski-Renic A, Belmonte-Beitia J, Pesic M and Calvo GF. (2019) Interplay of Darwinian Selection, Lamarckian induction and Microvesicle Transfer on Drug Resistance in Cancer. Sci Rep 9:9332.

https://doi.org/10.1038/s41598-019-45863-z