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Targeting tumor-stromal interactions in triple negative breast cancer using a human vascularized micro-tumor model

ABSTRACT: Targeting tumor-stromal interactions in triple negative breast cancer using a human vascularized micro-tumor model

PROVIDER: PRJNA997957 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25399700.fastq.gz	Fastqsanger.gz
	SRR25399701.fastq.gz	Fastqsanger.gz
	SRR25399702.fastq.gz	Fastqsanger.gz
	SRR25399703.fastq.gz	Fastqsanger.gz
	SRR25399704.fastq.gz	Fastqsanger.gz

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Targeting tumor-stromal interactions in triple negative breast cancer using a human vascularized micro-tumor model

Project description:Background: Triple-negative breast cancer (TNBC) is characterized by its highly aggressive pathology and limited number of approved targeted therapies. Emerging evidence suggests that stromal cells within the tumor microenvironment (TME) play a crucial role in TNBC progression, making them potential therapeutic targets. Yet the molecular basis of stromal cell activation and tumor-stromal crosstalk in TNBC is poorly understood, limiting the development of therapies targeted to this axis. Methods: To explore potential therapeutic targets within the stromal niche of TNBC, we employed an advanced human in vitro microphysiological system model – the vascularized microtumor (VMT) – in which perfused vascular networks within a microfluidic platform self-assemble in a complex extracellular matrix (ECM) and supply nutrients and drugs to growing tumors. By leveraging single-cell RNA sequencing (scRNA-seq), we investigated gene expression patterns, cellular heterogeneity, and intercellular communication within TNBCs. Results: Our analysis revealed that histopathologically-normal human breast tissue-derived stromal cells activate neoplastic signaling pathways when exposed to the TNBC TME. Through a comparison of these interactions in VMTs with scRNA-seq data obtained from clinical specimens, we successfully identified therapeutic targets situated at the tumor-stromal interface that hold potential clinical significance. Promising results were observed in TNBC VMTs when combining treatments that target Tie2 signaling, thereby normalizing vasculature, with tumor-targeted paclitaxel. Furthermore, dual inhibition of Her3 and Akt also demonstrated efficacy against TNBC. Conclusions: By using an organotypic in vitro VMT model to recapitulate key components of the TNBC TME, we demonstrate the potential of inducing a favorable tumor microenvironment as a targeted therapeutic approach in TNBC.

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An in vitro vascularized micro-tumor model of human colorectal cancer recapitulates in vivo responses to standard-of-care therapy

Project description:Around 95% of anti-cancer drugs that show promise during preclinical study fail to gain FDA-approval for clinical use. This failure of the preclinical pipeline highlights the need for improved, physiologically-relevant in vitro models that can better serve as reliable drug-screening and disease modeling tools. The vascularized micro-tumor (VMT) is a novel three-dimensional model system (tumor-on-a-chip) that recapitulates the complex human tumor microenvironment, including perfused vasculature, within a transparent microfluidic device, allowing real-time study of drug responses and tumor–stromal interactions. Here we have validated this microphysiological system (MPS) platform for the study of colorectal cancer (CRC), the second leading cause of cancer-related deaths, by showing that gene expression, tumor heterogeneity, and treatment responses in the VMT more closely model CRC tumor clinicopathology than current standard drug screening modalities, including 2-dimensional monolayer culture and 3-dimensional spheroids.

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Gene expression anlaysis of laser-capture microdissected tumor and stroma from triple negative breast cancer

Project description:LCM was perfomed on adjacent tumor and stromal cells to identify differentially expressed genes in triple negative breast cancer. To determine differences in tumor and adjacent stromal tissue, laser-capture microdissction was perfomed on 10 triple negative breast cancer specimans to isolate tumor and stromal cells for gene expression analysis. RNA was isolated from captured cells and hybridized to affymetrix gene expression microarrays.

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Identification of interacting stromal properties in triple-negative breast cancer - Stromal Discovery Set

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Project description:Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues’ thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by factors like cold exposure, share mechanisms that drive non-shivering thermogenesis. Understanding their behavior requires sophisticated, yet universal in vitro models that replicate the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue. We show that scaffold embedding improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to 2D cultures, which was further enhanced by β-adrenergic receptor stimulation via isoproterenol correlating with elevated β-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, our vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.

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Project description:Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor cell-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids comprised only with cancer cells. Notably, the hybrid spheroid also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip were interconnected with intratumoral vessels and displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer.

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