Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer

Abstract

Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with numerous epigenetic states in addition to stem-like and mesenchymal phenotypes, and the dynamic behavior of this heterogeneous mixture in response to drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified with intracellular markers such as cytokeratins, is linked to resistance to specific targeted therapeutics. Understanding the dynamics of differentiation-state transitions in this context could facilitate the development of more effective treatments for cancers that exhibit phenotypic heterogeneity and plasticity. In this work, we develop computational models of a drug-treated, phenotypically heterogeneous triple-negative breast cancer (TNBC) cell line to elucidate the feasibility of differentiation-state transition as a mechanism for therapeutic escape in this tumor subtype. Specifically, we use modeling to predict the changes in differentiation-state transitions that underlie specific therapy-induced changes in differentiation-state marker expression that we recently observed in the HCC1143 cell line. We report several statistically significant therapy-induced changes in transition rates between basal, luminal, mesenchymal, and non-basal/non-luminal/non-mesenchymal differentiation states in HCC1143 cell populations. Moreover, we validate model predictions on cell division and cell death empirically, and we test our models on an independent data set. Overall, we demonstrate that changes in differentiation-state transition rates induced by targeted therapy can provoke distinct differentiation-state aggregations of drug-resistant cells, which may be fundamental to the design of improved therapeutic regimens for cancers with phenotypic heterogeneity.

Interrogation of Phenotypic Plasticity between Epithelial and Mesenchymal States in Breast Cancer

“…Determinants of metastatic competency investigated by sequencing of primary tumors and metastases from various cancers, such as colorectal cancer and ovarian cancer, have been unable to link specific genetic alterations with tumor dissemination per se [42,80]. Intra-tumoral heterogeneity beyond genetic determinants also had clinical implications in chemotherapy response [81,82,83]. Both intra-tumoral heterogeneity and intrinsic cellular plasticity warrant consideration as important non-genomic factors that may contribute to dynamic cellular behaviors.…”

A Mechanism for Epithelial-Mesenchymal Heterogeneity in a Population of Cancer Cells

“…The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized. Some studies have described phenomenological models of phenotypic plasticity in cancer cells (Chapman et al, 2019;Gupta et al, 2011;Risom et al, 2018). While predictions from these models fit the experimental data reported in the respective studies, such models lack detailed biomolecular mechanistic bases.…”

Cancer stem cell and mesenchymal cell cooperative actions in metastasis progression and hormone resistance in prostate cancer: Potential role of androgen and gonadotropin‑releasing hormone receptors (Review)

“…It is well-known that epithelial-mesenchymal transition (EMT) is the main pathway via which malignant epithelial cells from carcinomas alter their gene expression profile to display a mesenchymal phenotype, acquiring, among other features, one of the hallmarks of cancer cells: Invasive behavior (34)(35)(36)(37)(38). However, increasing evidence indicates that tumors contain a phenotypically heterogeneous cell population, and that the cooperative action of these different types of malignant cells is potentially required to accomplish a successful metastatic process (39)(40)(41)(42). In the past few years, a small subpopulation of malignant cells with stem-like properties has been identified in numerous types of cancer, including PCa (43,44).…”