Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

Simultaneous evaluation of maspin and CXCR4 in patients with breast cancer.

AIM: To study simultaneously the actions of maspin and CXCR4, which share several similar pathways in cancer, including apoptosis and angiogenesis. METHODS: Our material consisted of 151 invasive breast carcinomas arranged in a tissue microarray setting. Maspin and CXCR4 expression was evaluated by immunohistochemistry. Microvessel density was assessed by CD34 immunodetection and apoptosis by the Tdt-mediated dUTP nick end labelling assay. RESULTS: Maspin expression was related to CXCR4 expression, apoptosis, patient age and the Nottingham prognostic index. The expression of both maspin and CXCR4 progressively increased in high-grade tumours. In patients with lymph node negative breast cancer, maspin overexpression was associated with increased risk of death. High CXCR4 expression was associated with prolonged survival of patients with high maspin expression. CONCLUSIONS: Our results show that maspin overexpression could prove to be a potentially useful marker, especially for the clinically important group of patients with lymph node negative breast cancer. The expression of CXCR4 is of less significance in our study, but may be informative for specific patient subsets or in a longer time frame.