A Systems Approach to Overcome Tumor-cell Heterogeneity in Drug Response: Metrics and Mechanisms
Comandante Lou, Natacha
2022
Abstract
Resistance due to tumor cell heterogeneity poses a major challenge to the use of targeted therapies for cancer treatment. Targeted therapies that are designed to block oncogenic signaling in tumor cells often yield substantial short-term responses but fail to fully eradicate tumors. Among the major barriers to full cures is the cell-to-cell heterogeneity in drug response that arises even among genetically identical cells. Recent single-cell studies have revealed that such non-genetic heterogeneity can prime a rare, transient subpopulation of tumor cells to be intrinsically drug-tolerant or render them cellular plasticity to adapt to drug-induced stress dynamically. These therapy escapees constitute a reservoir of reversibly drug-tolerant cells, which can then acquire more stably resistant phenotypes with continuous drug exposure, ultimately driving tumor relapse. Although the emergence and consequences of such intrinsic and adaptive heterogeneities are widely recognized, their molecular basis and their connection to variable states of drug sensitivity remain elusive. Furthermore, the dynamic responses of residual subpopulations of drug-tolerant cells are often obscured by fixed-time population-based measurements in most pre-clinical drug-response assays, posing another challenge to the design of effective therapeutic strategies to overcome drug resistance. The focus of this dissertation is to address these gaps in our knowledge by quantifying and dissecting the origins of cell-to-cell heterogeneity in cancer drug response using systems biology approaches. First, I developed new experimental and mathematical frameworks to evaluate time-dependent drug responses using probabilistic metrics that quantify drug-induced phenotypic events (i.e., cell death and division) at the single-cell level. By quantifying single-cell phenotypic events over time, these metrics provide a more accurate description of drug response for heterogeneous cell populations. Furthermore, these metrics can reveal which drugs or drug combinations have the ability to block rare subpopulations of drug-tolerant cells. Thus, they have important implications for designing efficacious treatments to avoid therapeutic escape. Second, this thesis investigates the molecular basis of cellular plasticity and non-genetic heterogeneity in drug response, focusing on the activator protein 1 (AP-1) transcription factor family, for their roles as key effectors of the mitogen-activated protein kinase (MAPK) pathway in BRAF-mutant cancers. Using BRAF-mutant melanoma as a model system with dysregulated MAPK signaling, I employed systems biology approaches that integrated data-driven modeling with multiplexed measurements to capture single-cell heterogeneity before and after MAPK inhibitor treatments in BRAF-mutated melanoma cells. I showed that the state of the AP-1 network plays a unifying role in explaining the intrinsic diversity of phenotypic states and adaptive responses to MAPK inhibitors. Perturbing the state of the AP-1 network through genetic depletion of specific AP-1 proteins, or by MAPK inhibitors, shifts cellular heterogeneity in a predictable fashion. Thus, AP-1 may serve as a critical node for manipulating cellular plasticity with potential therapeutic implications. Together, this thesis may facilitate future efforts for the rational design of therapeutic strategies that aim at overcoming the challenge of drug resistance arising due to tumor cell heterogeneity and plasticity.Deep Blue DOI
Subjects
Drug resistance Single-cell biology Tumor heterogeneity Drug interactions Cellular plasticity Melanoma
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