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) before 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 (CNAs). 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% vs 56%, P = .0029), progression-free survival (PFS; P = .0007; hazard ratio, 2.11), and overall survival (OS; P = .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 highly associated with poor outcomes, leading to inferior PFS (P < .0001; hazard ratio, 3.49) and OS (P = .0027; hazard ratio, 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated lactate dehydrogenase and >1 extranodal site), 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.

Low density lipoprotein receptor related protein-1 (LRP-1) is a large ubiquitous endocytic receptor mediating the clearance of various molecules from the extracellular matrix. Several studies have shown that LRP-1 plays crucial roles during tumorigenesis functioning as a main signal pathway regulator, especially by interacting with other cell-surface receptors. Discoïdin Domain Receptors (DDRs), type I collagen receptors with tyrosine kinase activity, have previously been associated with tumor invasion and aggressiveness in diverse tumor environments. Here, we addressed whether it could exist functional interplays between LRP-1 and DDR1 to control colon carcinoma cell behavior in three-dimensional (3D) collagen matrices. We found that LRP-1 established tight molecular connections with DDR1 at the plasma membrane in colon cancer cells. In this tumor context, we provide evidence that LRP-1 regulates by endocytosis the cell surface levels of DDR1 expression. The LRP-1 mediated endocytosis of DDR1 increased cell proliferation by promoting cell cycle progression into S phase and decreasing apoptosis. In this study, we identified a new molecular way that controls the cell-surface expression of DDR1 and consequently the colon carcinoma cell proliferation and apoptosis and highlighted an additional mechanism by which LRP-1 carries out its sensor activity of the tumor microenvironment.

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.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell malignancies and multiple myeloma, but its extension to T-cell lymphomas (TCLs) has been constrained by the paucity of antigens that can be safely targeted. While targeting pan-T antigens broadens the therapeutic reach across various TCLs, it carries a substantial risk of immunosuppression and infection. Here, we report killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR3DL2/CD158k) as a viable target for CAR T-cell therapy against a wide range of TCLs. Using single-cell RNA-seq data analysis and flow cytometric phenotyping, we observed that KIR3DL2 expression is restricted to a subset of mature NK cells and a minor fraction of CD8⁺ T cells, with negligible expression in other healthy adult tissues. Among TCLs, KIR3DL2 expression was noted in various subtypes of cutaneous and systemic TCLs. Anti-KIR3DL2 CAR constructs (3DL2CARs) efficiently and selectively redirected T cells against antigen-positive cell lines but not isogenic KIR3DL2-negative counterparts, with antigen-specific signaling, cytotoxicity, proliferation, and cytokine production. Importantly, 3DL2CART cells produced sustained tumor regression and prolonged survival in two distinct cell line-derived xenograft models of cutaneous TCL and in one patient-derived xenograft model of hepatosplenic TCL. 3DL2CART cells exhibited minimal off-target activity against bystander immune cells and showed no appreciable fratricide. To mitigate the risk of tumor cell contamination in autologous CAR T-cell products, we established a two-tiered strategy that integrates immunomagnetic depletion of KIR3DL2-positive tumor cells with in vivo activation of a safety switch if inadvertently transduced malignant cells contribute to immune escape. Together, our results establish the preclinical efficacy and safety of 3DL2CART-cell therapy and support its clinical translation. This approach may offer a targeted alternative to pan-T-cell-directed CAR T-cell strategies for patients with relapsed/refractory cutaneous and systemic TCLs, addressing a critical unmet clinical need.

Le récepteur low-density lipoprotein receptor-related protein-1 (LRP-1) est un récepteur d’endocytose multifonctionnel impliqué dans de nombreux processus physiologiques et pathologiques. Plusieurs études ont montré que LRP-1 joue un rôle crucial lors des processus de tumorigenèse et durant la progression tumorale, notamment en régulant l’expression de protéines membranaires. Des études antérieures ont montré l'implication des récepteurs du collagène de type I de la famille des Discoidin Domain Receptors (DDRs) dans la régulation de la prolifération des cellules cancéreuses en 3D. Le but de ce travail est d'étudier s’il existe une interaction fonctionnelle entre LRP-1 et DDR1 et si celle-ci pourrait moduler la prolifération des cellules de cancer colorectal (CRC) cultivées dans une matrice 3D de collagène de type I.Nos résultats ont permis de montrer qu'une invalidation de LRP-1 ou une inhibition de son activité par l’utilisation d’antagonistes sélectifs (RAP, anticorps bloquants) altère la prolifération des cellules de CRC LS174T et HT-29, uniquement lorsque qu’elles sont intégrées dans une matrice 3D de collagène de type I. De plus, la surexpression de DDR1-GFP dans les cellules HT-29 (HT-29DDR-GFP) diminue leur taux de croissance, tandis que l’inhibition de LRP-1 par RAP induit un arrêt du cycle cellulaire et une augmentation de l’apoptose dans les cellules HT-29 et HT-29DDR-GFP. Nous avons montré que la quantité de DDR1 à la surface cellulaire était augmentée et que l’endocytose de DDR1 était réduite de moitié lors du traitement par RAP, mettant ainsi en évidence une nouvelle voie d’internalisation pour DDR1. De plus, LRP-1 et DDR1 co-immunoprécipitent ensemble indiquant que ces récepteurs sont fortement associés au sein d’un même complexe moléculaire dans les cellules de CRC.Nos résultats mettent en évidence l’existence d’une interface fonctionnelle entre LRP-1 et DDR1 I soutenant la prolifération des cellules de CRC dans une matrice 3D de collagène.