The Cancer Progression Center of Excellence (CPC) integrates the research energy of National Yang Ming Chiao Tung University (NYCU) and Taipei Veterans General Hospital (TVGH) with a solid foundation supported by Ministry of Education, Taiwan. The main goal of the Center is to explore novel mechanisms in cancer progression and try to translate the results into clinical practice. The major efforts of CPC are made for the establishment of the platform of circulating tumor cells isolation and detection, single-cell sequencing, multispectral imaging, and spatial transcriptomics analysis for analysis of the tumor cells and immune cells in tumor microenvironments (TME). These platform developments will provide essential tools to study the functional crosstalk between immune cells, cancer stem cell, and cancer cell movement in TME during cancer progression. Overall, the Center will continue to conduct in-depth basic and translational researches of cancer progression by asking the major clinical questions.
The tumor microenvironment (TME) consists of a heterogeneous group of tumor cells together with a variety of other host cells, all of which actively participate within the tumor-host interface as part of disease aggression/progression. The extracellular structural and cellular molecular patterning of these many types of cell not only dictate the niche configuration of the tumor, but also contribute to anti-tumor immunity, which in turn leads to therapeutic heterogeneity. Colorectal cancer (CRC) is one of the most common cancers worldwide and it has high cancer-related mortality. The disease progression of CRC is tightly associated with an aberrant activation of an intestinal stem cell (ISC) signature and the presence of cancer stem cells (CSCs). We have found that colorectal cancer stem cells (CRCSCs) undergo the epithelial-to-mesenchymal transition (EMT) with Snail being the predominant EMT regulator; this results in cancer stemness and allows symmetrical cell division (SCD) to expand the CSC pool. Tumor-infiltrating neutrophils are initially educated by the CSC-exosomes and then are recruited by CSC-chemokines; this subsequently allows the development of a permissive tumor and an immunosuppressive TME.
Cancer Cell Movement
The acquisition of the ability of cancer cells to migrate in a complex three-dimension environment is one of important characteristics of tumor malignancy. Different types of cancer cells are able to migrate via different modalities; these include mesenchymal cell migration, amoeboid cell migration, and collective cell migration. However, the underlying mechanisms remain elusive. The goal of this subproject is to understand the molecular mechanisms behind cancer cell migration via a multidisciplinary approach, including an in vitro 3D culture platform, advanced microscope technology, ‘omics approaches, animal models, and clinical studies. Understanding how cancer cells migrate in vivo should provide new ways of intervening in the disease as part of cancer therapy. Cell migration in a complex three-dimension environments is a complicated process that requires the coordinated regulation of many cellular activities, including gene regulation, post-translational modification, cytoskeletal dynamics, cell adhesion, cell contractility, extracellular matrix remodeling, and other systems. To better understand these alterations in the biophysical properties of cancer cells during cell migration, advanced live-cell microscopy is being developed to analyze cell rigidity, cellular deformability, cellular contractility, and the ability of cells to remodel extracellular collagen fibers.
Cancer Stem Cell
Cancer stem cells (CSCs) and cancer initiating cells make up only a small part of the cancer cell population within heterogeneous tumors, but, nevertheless, they are considered to play a central role in the development of drug resistance and thence cancer relapse. Researchers at NYCU has applied the concept of reprogramming to cancer cells and has identified several key pathways that are directly involved in cancer malignancy and relapse, as well as identifying various key regulators of cancer stemness that are suitable therapeutic targets. One such is miR-142-3p, which regulates the properties of CSCs and the cancer reprogramming step. Suppression of the expression of miR-142-3p leads to the recurrence and progression of glioblastoma (GBM); while a reactivation of miR142-3p expression blocks the protein synthesis pathways for IL-6, HMGA2, and Sox2 during GBM-reprogramming, and prevents GBM recurrence. NYCU scientists has discovered an IL-6-dependent positive-feedback loop that is active in GBM and this suggests that the IL-6/miR-142-3p signaling pathway is a prospective therapeutic target for the treatment of GBM. His discovery, with its prospect of clinical applications, is a step forward in terms of GBM therapy.