The Cancer Stem Cell Fraction in Hierarchically Organized Tumors Can Be Estimated Using Mathematical Modeling and Patient-Specific Treatment Trajectories

Abstract

Many tumors are hierarchically organized and driven by a sub-population of tumor initiating cells (TICs), or cancer stem cells. TICs are uniquely capable of recapitulating the tumor and are implied to be highly resistant to radio- and chemotherapy. Macroscopic patterns of tumor expansion before treatment and tumor regression during treatment are tied to the dynamics of TICs. Until now, quantitative information about the fraction of TICs from macroscopic tumor burden trajectories could not be inferred. In this study, we generated a quantitative method based on a mathematical model that describes hierarchically organized tumor dynamics and patient-derived tumor burden information. The method identifies two characteristic equilibrium TIC regimes during expansion and regression. We show that tumor expansion and regression curves can be leveraged to infer estimates of the TIC fraction in individual patients at detection and after continued therapy. Furthermore, our method is parameter-free; it solely requires knowledge of a patient’s tumor burden over multiple time points to reveal microscopic properties of the malignancy. We demonstrate proof of concept in the case of chronic myeloid leukemia (CML), wherein our model recapitulated the clinical history of the disease in two independent patient cohorts. Based on patient-specific treatment responses in CML, we predict that after one year of targeted treatment, the fraction of TICs increases 100-fold and continues to increase up to 1000-fold after five years of treatment. Our novel framework may significantly influence the implementation of personalized treatment strategies and has the potential for rapid translation into the clinic.

Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy

“…These experiments led us to hypothesize that the cellular hierarchy of the tumor (12,13) might be an important factor determining tumor sensitivity to chemotherapy. Tumors are known to retain certain features of normal tissue cell hierarchy (14).…”

“…This is supported by the notion that they are maintained by a subpopulation of tumor stem cells (15), and that the bulk of the tumor contains more differentiated cancer cells that by themselves cannot maintain or initiate a new tumor. Recent work further suggests that positive and negative feedback loops regulating normal tissue might remain active to a certain extent in tumors (13). The aforementioned wound-healing response (10) is an example of a positive feedback loop.…”

An exactly solvable, spatial model of mutation accumulation in cancer

“…in ref. 60. This assumption would affect the growth rate and the rate at which mutations accumulate in a single lesion.…”

Hierarchical Tissue Organization as a General Mechanism to Limit Somatic Evolution

“…Models that integrate information on tissue organization have not only provided novel insight into cancer as an evolutionary process [27,36,37], but have also produced direct predictions for improved treatment [38][39][40]. The simple and intuitive relations that we derive below have the potential to further this field of research by providing quantitative grounds for the deep connection between organization principles of tissues and disease prevention and treatment.…”