Search

The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy. We use breast cancer and glioblastoma as instructive examples and highlight how invasion in both diseases is driven by the appropriation of structural guidance cues, contact-dependent heterotypic interactions with stromal cells, and elevated interstitial fluid pressure and flow. We discuss how engineering strategies show increasing value for measuring and modeling these physical propertiesfor mechanistic studies. Moreover, engineered systems offer great promise for developing and testing novel therapies that improve patient prognosis by normalizing the physical tumor microenvironment.

Breast cancer metastasis is initiated by invasion of tumor cells into the collagen type I-rich stroma to reach adjacent blood vessels. Prior work has identified that metabolic plasticity is a key requirement of tumor cell invasion into collagen. However, it remains largely unclear how blood vessels affect this relationship. Here, we developed a microfluidic platform to analyze how tumor cells invade collagen in the presence and absence of a microvascular channel. We demonstrate that endothelial cells secrete pro-migratory factors that direct tumor cell invasion toward the microvessel. Analysis of tumor cell metabolism using metabolic imaging, metabolomics, and computational flux balance analysis revealed that these changes are accompanied by increased rates of glycolysis and oxygen consumption caused by broad alterations of glucose metabolism. Indeed, restricting glucose availability decreased endothelial cell-induced tumor cell invasion. Our results suggest that endothelial cells promote tumor invasion into the stroma due, in part, to reprogramming tumor cell metabolism. [ABSTRACT FROM AUTHOR]

Breast cancer bone metastasis is the leading cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Here, we investigate how bone mineral content affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to matrix mineral content depends on host immunocompetence and the murine tumor model used. Collectively, our findings suggest that bone mineral density affects tumor growth by altering microenvironmental complexity in an organism-dependent manner., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.

Skeletal metastasis is common in patients with advanced breast cancer and often caused by immune evasion of disseminated tumor cells (DTCs). In the skeleton, tumor cells not only disseminate to the bone marrow but also to osteogenic niches in which they interact with newly mineralizing bone extracellular matrix (ECM). However, it remains unclear how mineralization of collagen type I, the primary component of bone ECM, regulates tumor-immune cell interactions. Here, a combination of synthetic bone matrix models with controlled mineral content, nanoscale optical imaging, and flow cytometry are utilized to evaluate how collagen type I mineralization affects the biochemical and biophysical properties of the tumor cell glycocalyx, a dense layer of glycosylated proteins and lipids decorating their cell surface. These results suggest that collagen mineralization upregulates mucin-type O-glycosylation and sialylation by tumor cells, which increases their glycocalyx thickness while enhancing resistance to attack by natural killer (NK) cells. These changes are functionally linked as treatment with a sialylation inhibitor decreased mineralization-dependent glycocalyx thickness and made tumor cells more susceptible to NK cell attack. Together, these results suggest that interference with glycocalyx sialylation may represent a therapeutic strategy to enhance cancer immunotherapies targeting bone-metastatic breast cancer., (© 2024 Wiley-VCH GmbH.)

P-glycoprotein (P-gp) is a promiscuous small molecule transporter whose overexpression in cancer is associated with multidrug resistance (MDR). In these instances, anticancer drugs can select for P-gp-overexpressing cells, leading to cancer recurrence with an MDR phenotype. To avoid selection for MDR cancers and inform individual patient treatment plans, it is critical to noninvasively identify P-gp-overexpressing tumors prior to administration of chemotherapy. We report the facile free radical copolymerization of quinidine, a competitive inhibitor of P-gp, and acrylic acid to generate multiplexed polymeric P-gp-targeted imaging agents with tunable quinidine content. Copolymer targeting was demonstrated in a nude mouse xenograft model. In xenografts overexpressing P-gp, copolymer distribution was enhanced over two-fold compared to the negative control of poly(acrylic acid) regardless of quinidine content. In contrast, accumulation of the copolymers in xenografts lacking P-gp was equivalent to poly(acrylic acid). This work forms the foundation for a unique approach toward the phenotype-specific noninvasive imaging of MDR tumors and is the first in vivo demonstration of copolymer accumulation through the active targeting of P-gp.