LRP-1 Promotes Colon Cancer Cell Proliferation in 3D Collagen Matrices by Mediating DDR1 Endocytosis

Abstract

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 cellsurface 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.

Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

“…In MDA‐MB‐231 breast cancer cells, DDR1 induced invasion through upregulation of MMP‐2 and MMP‐9 secretion 55 . Studies have also found that overexpression of DDR1 can induce invasion of colon carcinoma cells through upregulation of MMP‐2 56 . For DDR2, a recent study demonstrated that DDR2 inhibition can decrease invasion of B16BL6 melanoma cells by suppressing MMP‐2 and MMP‐9 expression via the ERK/NF‐κB pathway 57 .…”

“…55 Studies have also found that overexpression of DDR1 can induce invasion of colon carcinoma cells through upregulation of MMP-2. 56 For DDR2, a recent study demonstrated that DDR2 inhibition can decrease invasion of B16BL6 melanoma cells by suppressing MMP-2 and MMP-9 expression via the ERK/NF-κB pathway. 57 However, researchers showed that downregulated DDR2 in mouse B16-F10 melanoma cells had no effect on lung metastasis.…”

Collagen and Discoidin Domain Receptor 1 Partnership: A Multifaceted Role in the Regulation of Breast Carcinoma Cell Phenotype

“…DDR1 silencing or interfering with its tyrosine kinase activity by using pharmacological inhibitors prevented the induction the BIK-dependent apoptotic process in the luminal-like cell lines (Assent et al, 2015;Saby et al, 2018), supporting a critical role for DDR1 in 3D COL1-induced apoptosis. A similar pro-apoptotic function of DDR1 was demonstrated in HT-29 colon carcinoma cells encapsulated in 3D COL1 (Le et al, 2020). These observations contrast with the classical concept that DDR1 expression in cancer cells is associated with an increased cell survival and proliferation (for review, see Majo and Auguste, 2021).…”

Discoidin Domain Receptor 1 Expression in Colon Cancer: Roles and Prognosis Impact

“…HCT116, SW480, SW620 and HT-29 colorectal carcinoma cell lines were purchased from American Type Culture Collection (ATCC, Rockville, MD, USA). HT-29DDR1-GFP and HT-29GFP were obtained as previously described [ 27 ]. All cell lines were grown in Dulbecco’s Modified Eagle Medium (DMEM) with high glucose (4.5 g/L) (Thermo Fisher Scientific, Villebon sur Yvette, France) containing 10% ( v / v ) fetal bovine serum (FBS) (Dutscher, Bernolsheim, France) and 1% penicillin-streptomycin ( v / v , Invitrogen).…”

“…Total RNA from cells was extracted as described previously [ 28 ] and single-stranded cDNA was synthesized from 250 ng total mRNAs using VERSO cDNA kit (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions. Determination of the mRNA of DDR1 was carried out by real-time PCR as described [ 27 ].…”