Extracellular matrix drives tumor organoids toward desmoplastic matrix deposition and mesenchymal transition

Cholangiocarcinoma (CCA) is a highly aggressive tumor which arises from the biliary duct epithelium. It is associated with a low 5-year survival rate, due to its biological complexity, late-stage diagnosis, and limited treatment options [1]. This malignant phenotype is related to the complex interplay between cells, both primary and stromal/immune, and extracellular matrix. Particularly in CCA, the dysregulation of the extracellular environment through extracellular matrix (ECM) remodeling, characterized by desmoplasia, is a vital aspect of cancer progression [2]. Understanding the biology behind the interaction of primary tumor cells with their tissue microenvironment may lead to more effective targeted therapies for cancer patients.

However, clinical translation of basic research on this topic is hindered by several obstacles. An intrinsic limitation often found in experimental systems is the lack of faithful recapitulation of interpatient cellular heterogeneity, a particularly important issue in CCA [3]. Thus, to capture the underlying mechanisms at play, it is crucial to use primary patient-modelling cancer cells and ECM. CCA organoids (CCAO) have been successfully established and have demonstrated to be promising in vitro patient-specific tumor models [4]. Until now, organoid-based research has focused on expanding the possibilities of obtaining CCAOs, performing high throughput drug screening, and identifying cancer gene functionality [5, 6]. However, these organoids have an inherent limitation since they consist solely of epithelial-sourced cells. More recently, multiple studies have combined tumor organoids with components of their tumor micro-environment, including immune and stromal cells [7, 8]. Although very useful, these models lack native tissue structures and ECM components that are typically associated with CCA. The chemical and mechanical cues from the ECM are key drivers in various crucial aspects of cancer, including initiation, progression, and metastasis [9]. Decellularization techniques have allowed for the isolation of native patient-derived extracellular matrix with preserved tissue architecture [10, 11], providing a source for more physiologically accurate scaffolds. Several studies using decellularized material have primarily used cancer cell lines to model cellular behavior, limiting applicability [12], [13], [14]. Thus, combining tumor organoids with ECM could elucidate more about the role of primary epithelial cells in the remodeling of ECM within CCA.

Here, we describe an in vitro model using patient-derived CCAOs in combination with decellularized CCA matrix (CCA-M) and tumor-free liver matrix (TFL-M) to study the interaction of tumor cells with their surrounding ECM. The scaffolds retain many of the physiological environmental cues of the (tumor) microenvironment. Our results show that CCA-M induces a transcriptome profile closely resembling in vivo patient tumor tissue with an accompanying chemo resistance in CCAOs. Furthermore, migration and proliferation dynamics are environment-specific, and related to the induction of epithelial-mesenchymal transition (EMT). Lastly, primary epithelial tumor cells can, in the absence of desmoplasia, initiate a desmoplastic reaction through increased collagen production (e.g. COL1A1, COL3A1, COL6A3), while, in the presence of desmoplasia, produce a distinct ECM-related protein signature linked to patient survival.

留言 (0)

沒有登入
gif