Abstract
Resistance to anti-cancer drugs is a major cause of treatment failure. While several intracellular mechanisms of resistance have been postulated, the role of extrinsic factors in the development of resistance in individual tumor cells is still not fully understood. Here we used a hybrid agent-based model to investigate how sensitive tumor cells develop drug resistance in the heterogeneous tumor microenvironment. We characterized the spatio-temporal evolution of lineages of the resistant cells and examined how resistance at the single-cell level contributes to the overall tumor resistance. We also developed new methods to track tumor cell adaptation, to trace cell viability trajectories and to examine the three-dimensional spatio-temporal lineage trees. Our findings indicate that drug-induced resistance can result from cells adaptation to the changes in drug distribution. Two modes of cell adaptation were identified that coincide with microenvironmental niches—areas sheltered by cell micro-communities (protectorates) or regions with limited drug penetration (refuga or sanctuaries). We also recognized that certain cells gave rise to lineages of resistant cells (precursors of resistance) and pinpointed three temporal periods and spatial locations at which such cells emerged. This supports the hypothesis that tumor micrometastases do not need to harbor cell populations with pre-existing resistance, but that individual tumor cells can adapt and develop resistance induced by the drug during the treatment.
Highlights
Drug resistance is one of the main impediments in effective anti-cancer therapy
The rest of the paper is devoted to analysis of resistance at the individual cell level, whether spatial structure of the microenvironment play a role in the emergence of resistance, and which cell lineages drive resistance of the whole tumor
We presented here a study analyzing how resistant cell lineages arise in micrometastases exposed to a systemic chemotherapeutic treatment
Summary
Drug resistance is one of the main impediments in effective anti-cancer therapy. While tumors may first respond well to chemotherapeutic agents, they often start growing back during or after the treatment period and become tolerant to the treatment. A pivotal role can be played by the tumor microenvironment [4, 5] due to reciprocal communication between tumor cells and the surrounding stromal components This includes interactions with fibroblasts and emergence of cancer associated fibroblasts, cross-talk with immune cells and sensing cues from the extracellular matrix (ECM), as well as ECM remodeling. The changes in tumor vasculature and interstitial fluid pressure may lead to creation of regions that are poorly penetrated by therapeutics, forming drug-limited pharmacologic sanctuaries or refugia [9, 10] that influence tumor response to therapeutics. These extrinsic factors are still not well understood
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