All biological systems exhibit cell-to-cell variability. Frameworks exist for understanding how stochastic fluctuations and transient differences in cell state contribute to experimentally observable variations in cellular responses. However, current methods do not allow identification of the sources of variability between and within stable subpopulations of cells. We present a data-driven modeling framework for the analysis of populations comprising heterogeneous subpopulations. Our approach combines mixture modeling with frameworks for distribution approximation, facilitating the integration of multiple single-cell datasets and the detection of causal differences between and within subpopulations. The computational efficiency of our framework allows hundreds of competing hypotheses to be compared. We initially validate our method using simulated data with an understood ground truth, then we analyze data collected using quantitative single-cell microscopy of cultured sensory neurons involved in pain initiation. This approach allows us to quantify the relative contribution of neuronal subpopulations, culture conditions, and expression levels of signaling proteins to the observed cell-to-cell variability in NGF/TrkA-initiated Erk1/2 signaling.
Melanoma is one of the deadliest cancers, yet the cells of origin and mechanisms of tumor initiation remain unclear. The majority of melanomas emerge from clear skin without a precursor lesion, but it is unknown whether these melanomas can arise from melanocyte stem cells (MCSCs). Here we employ mouse models to define the role of MCSCs as melanoma cells of origin, demonstrate that MCSC quiescence acts as a tumor suppressor, and identify the extrinsic environmental and molecular factors required for the critical early steps of melanoma initiation. Specifically, melanomas originate from melanoma-competent MCSCs upon stimulation by UVB, which induces MCSC activation and translocation via an inflammation-dependent process. Moreover, the chromatin-remodeling factor Hmga2 in the skin plays a critical role in UVB-mediated melanomagenesis. These findings delineate melanoma formation from melanoma-competent MCSCs following extrinsic stimuli, and they suggest that abrogation of Hmga2 function in the microenvironment can suppress MCSC-originating cutaneous melanomas.