Modeling the Effect of the Metastatic Microenvironment on Phenotypes Conferred by Estrogen Receptor Mutations Using a Human Liver Microphysiological System

Mark T Miedel,Andrew M Stern,Albert Gough,Shanhang Jia,Dillon C Gavlock,D Lansing Taylor

doi:10.1038/s41598-019-44756-5

Abstract

Reciprocal coevolution of tumors and their microenvironments underlies disease progression, yet intrinsic limitations of patient-derived xenografts and simpler cell-based models present challenges towards a deeper understanding of these intercellular communication networks. To help overcome these barriers and complement existing models, we have developed a human microphysiological system (MPS) model of the human liver acinus, a common metastatic site, and have applied this system to estrogen receptor (ER)+ breast cancer. In addition to their hallmark constitutive (but ER-dependent) growth phenotype, different ESR1 missense mutations, prominently observed during estrogen deprivation therapy, confer distinct estrogen-enhanced growth and drug resistant phenotypes not evident under cell autonomous conditions. Under low molecular oxygen within the physiological range (~5–20%) of the normal liver acinus, the estrogen-enhanced growth phenotypes are lost, a dependency not observed in monoculture. In contrast, the constitutive growth phenotypes are invariant within this range of molecular oxygen suggesting that ESR1 mutations confer a growth advantage not only during estrogen deprivation but also at lower oxygen levels. We discuss the prospects and limitations of implementing human MPS, especially in conjunction with in situ single cell hyperplexed computational pathology platforms, to identify biomarkers mechanistically linked to disease progression that inform optimal therapeutic strategies for patients.

Highlights

Www.nature.com/scientificreports cells within the heterogeneous tumor microenvironment (TME)[16,17,18]
The cell types used in both the static co-culture and Liver Acinus MicroPhysiological System (LAMPS) models are (Table S1): primary human hepatocytes, human endothelial, Kupffer and stellate cell lines and the number of each cell type seeded in each model
Whereas the majority of breast cancer liver metastases had a replacement growth pattern in which cancer cells grow in continuity with hepatocytes, only a small percentage of colorectal metastases grew via this pattern

Summary

Introduction

Www.nature.com/scientificreports cells within the heterogeneous tumor microenvironment (TME)[16,17,18]. A better understanding of how cancer cells behave and function within the metastatic microenvironment is critical to the translational objective of defining the signaling networks within the TME that lead to the identification of 1) specific biomarkers mechanistically linked to metastatic disease and 2) targetable tumor dependencies that can inform novel therapeutic strategies. Prominent in this paradigm has been the use of patient-derived xenograft (PDX) mouse models for testing causal hypotheses generated from the molecular characterization of the TME in clinical samples[19]. Controlled variation of critical parameters in evolving human liver MPS that otherwise is not achievable in PDX mouse models, will facilitate the identification and preclinical validation of biomarkers mechanistically linked to malignant disease progression as well as inform novel therapeutic strategies that may include agents that target specific mutant ESR1 expressing clones or that directly modify the TME

Objectives

Results

Conclusion