Colorectal cancer is the second most common cancer diagnosed in men and the third most commonly occurring in women worldwide. Interactions between cells and the surrounding extracellular matrix (ECM) are involved in tumor development and progression of many types of cancer. The organization of the ECM molecules provides not only physical scaffoldings and dynamic network into which cells are embedded but also allows the control of many cellular behaviors including proliferation, migration, differentiation, and survival leading to homeostasis and morphogenesis regulation. Modifications of ECM composition and mechanical properties during carcinogenesis are critical for tumor initiation and progression. The core matrisome consists of five classes of macromolecules, which are collagens, laminins, fibronectin, proteoglycans, and hyaluronans. In most tissues, fibrillar collagen is the major component of ECM. Cells embedded into fibrillar collagen interact with it through their surface receptors, such as integrins and discoidin domain receptors (DDRs). On the one hand, cells incorporate signals from ECM that modify their functionalities and behaviors. On the other hand, all cells within tumor environment (cancer cells, cancer-associated fibroblasts, endothelial cells, and immune cells) synthesize and secrete matrix macromolecules under the control of multiple extracellular signals. This cell-ECM dialog participates in a dynamic way in ECM formation and its biophysical and biochemical properties. Here, we will review the functional interplay between cells and collagen network within the tumor microenvironment during colorectal cancer progression.

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low pass whole genome sequencing (lpWGS) of cell free DNA (cfDNA) prior to CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNA). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% versus 56%, p=0.0029), progression free survival (PFS) (p=0.0007, hazard ratio 2.11) and overall survival (OS) (p=0.0026, hazard ratio 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most prognostic for poor outcomes, leading to inferior PFS (p<0.0001, hazard ratio 3.49) and OS (p=0.0027, hazard ratio 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated LDH and >1 extranodal sites), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials.

Extracellular matrix components such as collagens are deposited within the tumor microenvironment at primary and metastatic sites and are recognized to be critical during tumor progression and metastasis development. This study aimed to evaluate the clinical and prognostic impact of Discoidin Domain Receptor 1 (DDR1) expression in colon cancers and its association with a particular molecular and/or morphological profile and to evaluate its potential role as a prognosis biomarker. Immunohistochemical expression of DDR1 was evaluated on 292 colonic adenocarcinomas. DDR1 was highly expressed in 240 (82.2%) adenocarcinomas. High DDR1 immunostaining score was significantly associated, on univariate analysis, with male sex, left tumor location, BRAF wild type status, KRAS mutated status, and Annexin A10 negativity. High DDR1 immunohistochemical expression was associated with shorter event free survival only. Laser capture microdissection analyses revealed that DDR1 mRNA expression was mainly attributable to adenocarcinoma compared to stromal cells. The impact of DDR1 expression on cell invasion was then evaluated by modified Boyden chamber assay using cell types with distinct mutational profiles. The invasion capacity of colon adenocarcinoma is supported by DDR1 expression. Thus, our results showed that DDR1 was highly expressed in most colon adenocarcinomas and appears as an indicator of worse event free survival.