Tumor‐stroma interactions differentially alter drug sensitivity based on the origin of stromal cells

Abstract

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large‐scale coculture assay optimized to measure drug‐induced cell death, we identify tumor–stroma interactions that modulate drug sensitivity. Our data show that the chemo‐insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor–stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.

Applicability of drug response metrics for cancer studies using biomaterials

“…The presence of stromal cells (cancer-associated fibroblasts, pericytes, or adipocytes) has been shown to drastically alter drug response, ranging from promoting drug resistance to increasing drug sensitivity [39][40][41][42][43][44]. Using multicellular cultures can account for tissue level interactions and therefore may be more physiologically relevant than monocultures.…”

“…Using multicellular cultures can account for tissue level interactions and therefore may be more physiologically relevant than monocultures. In fact, it was recently shown that basal-like and mesenchymallike subclasses of breast cancer could be distinguished based on their expected drug sensitivities, but only in fibroblast co-cultures [40]. While it is currently unclear how much complexity is required to accurately predict in vivo drug efficacy, studies that incorporate multiple cell types within biomaterials help to reveal the benefits of multifaceted models [41].…”

Three‐dimensional culture models to study drug resistance in breast cancer

“…Coculture of carcinoma cells with stromal cells reveals additional ways breast cancer cells avoid drug‐induced autophagy. Using basal‐like or mesenchymal‐like TNBC cell lines together with normal primary fibroblasts or CAFs in Matrigel, the presence of stromal cells was found to alter the mitochondrial priming state of cancer cells based on the drug administered, cancer subtype and, occasionally, stromal cell line (Landry et al, 2018). Little difference in influence was seen between normal fibroblasts and CAFs.…”

“…Little difference in influence was seen between normal fibroblasts and CAFs. Because some combinations resulted in positive response and others negative, there was no consistent trend observed in drug response (Landry et al, 2018). This highlights the importance of model selection for drug testing.…”

A biomimetic liver model recapitulating bio-physical properties and tumour stroma interactions in hepatocellular carcinoma

“…The resulting fibrosis in turn causes the dysregulation of extracellular matrix remodeling enzyme activity, creating an environment characterized by an overall increased stiffness accompanied by the secretion of growth factors, which further contributes to HCC pathogenesis (Hernandes-Gea et al ., 2013; Amicone & Marchetti, 2018). It is this continuous pathogenic feedback loop between hepatocytes and the stromal environment, which fuels cancer initiation, epithelial to mesenchymal transitions (EMT), metastatic potential, and altered drug response (Rawal et al ., 2019; Yoo et al ., 2017; Landry et al ., 2018). Insight into hepatocarcinogenesis in terms of the interplay between the tumor and the tumor micro-environment is thus of considerable importance not only from a mechanistic but also from a treatment perspective.…”