O'Neill, J. D. | Search bioRxiv

bioRxiv2021

Targeting metabolic adaptations in the breast cancer liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ER activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. ImplicationsOur findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

cancer biology↗

bioRxiv2019

Fibrotic human lung extracellular matrix as a disease-specific substrate for 3D in-vitro models of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an irreversible and uniformly fatal lung disease marked by destruction and scarring of the lung parenchyma and progressive loss of respiratory function. IPF affects nearly 3 million people worldwide, and annual mortality in the US alone exceeds 40,000. Nintedanib and pirfenidone, the only drugs approved for the treatment of IPF, slow progression but do not cure the disease. Consequently, there is a pressing need for effective treatments beside lung transplantation. Unfortunately, predictive models of IPF are not available, underscoring the critical need for physiologically relevant in-vitro substrates that enable quantitative and mechanistic studies of human IPF. Here we report the development and characterization of a human pulmonary fibrosis-specific cell culture substrate comprised of intact fibrotic lung extracellular matrix that recapitulates the human IPF disease environment in vitro. We document the activation and disease-specific phenotype of human lung fibroblasts cultured in the IPF disease-specific substrate, and establish feasibility of testing antifibrotic agents using this substrate. Altogether, our results demonstrate the applicability of this fibrosis-specific substrate for 3D in-vitro models of IPF and cell-based assays in early-stage drug discovery.

cell biology↗