Cell-in-Cell Structure Mediates In-Cell Killing Suppressed by CD44
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ABSTRACT:
PROVIDER: PRJNA733823 | ENA |
REPOSITORIES: ENA
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Project description:Penetration of immune cells into tumor cells was believed to be immune-suppressive via cell-in-cell (CIC) mediated death of the internalized immune cells. We unexpectedly found that CIC formation largely led to the death of the host tumor cells, but not the internalized immune cells, manifesting typical features of death executed by NK cells, which we called “in-cell killing” that demonstrates efficacy superior to the canonical way of “kiss killing” from outside. By expression profiling of isogenic cells, CD44 on tumor cells was identified as a negative regulator of “in-cell killing” via inhibiting CIC formation. CD44 functions to antagonize NK cell internalization by reducing N-cadherin-mediated intercellular adhesion and enhancing Rho GTPase-regulated cellular stiffness as well. Remarkably, antibody-mediated blockade of CD44 signaling potentiated the suppressive effects of NK cells on tumor growth associated with increased heterotypic CIC formation. Together, we identified CIC-mediated “in-cell killing” as a promising strategy for cancer immunotherapy.
2024-05-20 | GSE175819 | GEO
Project description:Penetration of immune cells into tumor cells was believed to be immune-suppressive via cell-in-cell (CIC) mediated death of the internalized immune cells. We unexpectedly found that CIC formation largely led to the death of the host tumor cells, but not the internalized immune cells, manifesting typical features of death executed by NK cells; we named this "in-cell killing" which displays the efficacy superior to the canonical way of "kiss-killing" from outside. By profiling isogenic cells, CD44 on tumor cells was identified as a negative regulator of "in-cell killing" via inhibiting CIC formation. CD44 functions to antagonize NK cell internalization by reducing N-cadherin-mediated intercellular adhesion and by enhancing Rho GTPase-regulated cellular stiffness as well. Remarkably, antibody-mediated blockade of CD44 signaling potentiated the suppressive effects of NK cells on tumor growth associated with increased heterotypic CIC formation. Together, we identified CIC-mediated "in-cell killing" as a promising strategy for cancer immunotherapy.
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Project description:To understand the role of p53 in regulating stem cell population (CD24-CD44+) and stemness-associated miRNAs, we first compared miRNA expression profiles between human mammary epithelical cells knocked-down p53 and control cells. We then cross-referenced p53-regulated miRNAs with stemness-associated miRNAs analyzed from expression profiling of sorted CD24-CD44+ and non-CD24-CD44+ cell populations. Further biological experiments were performed with the miRNAs that are altered in CD24-CD44+ stem cell populations and also regulated by p53. Total RNAs, including miRNAs, extracted from CD24-CD44+ cells (labeled in Hy3) and non-CD24-CD44+ cells (labeled in Hy5) were hybridized on Exiqon miRCURY LNA arrays according to the manufacturer's protocol.
2011-02-01 | E-GEOD-25036 | biostudies-arrayexpress
Project description:To understand the role of p53 in regulating stem cell population (CD24-CD44+) and stemness-associated miRNAs, we first compared miRNA expression profiles between human mammary epithelical cells knocked-down p53 and control cells. We then cross-referenced p53-regulated miRNAs with stemness-associated miRNAs analyzed from expression profiling of sorted CD24-CD44+ and non-CD24-CD44+ cell populations. Further biological experiments were performed with the miRNAs that are altered in CD24-CD44+ stem cell populations and also regulated by p53.
2011-02-01 | GSE25036 | GEO
Project description:CD44 is a transmembrane glycoprotein playing a key role in cel adhesion to the extracellular matrix. CD44 expression is upregulated in various cancer cells and recognized as a molecular marker for tumor-initiating cancer cells. However, the intricate correlation between CD44 and underlying biological functions is yet to be fully disclosed at molecular levels. Here, we discovererd global proteome changes induced by CD44 knockdown in the four different breast cancer cell lines by TMT based quantitative proteomics.
2021-06-10 | PXD015171 | Pride
Project description:To identify genes that are differentially expressed between CD44+ and CD44- cells in colonospheres, we have employed whole genome microarray expression profiling as a discovery platform. Colonospheres from four colon cancer patients were sorted into CD44+ and CD44- cells using the FACS Aria II Cell Sorter, and total RNA extracted from the cells were labeled with Cy3 and used for microarray analyses with Agilent Whole Human Genome Oligo Microarrays. Gene expression in fluorescence-activated cell-sorted CD44+ and CD44- cells derived from four colon cancer patients was measured.
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Project description:Natural killer (NK) cell-based immunotherapies represent a promising avenue for cancer treatment due to their ability to eliminate cancer cells independently of antigen presentation and potential for “off-the-shelf” use. However, the molecular determinants governing tumor cell susceptibility to NK cell-mediated cytotoxicity remain incompletely understood. Here we employed CRISPR activation (CRISPRa) screening to systematically identify cancer cell surface regulators of NK cell killing across multiple cancer types. Using a comprehensive surfaceome-focused library, we screened human and murine cancer cell lines co-cultured with NK cells, identifying both known and novel ligands that modulate NK cell cytotoxicity. Our screens revealed established factors including CD43 (encoded by SPN), while uncovering previously uncharacterized regulators such as CD44, PDPN, and Siglec-1/CD169. Validation through complementary cDNA overexpression and genetic knockout approaches confirmed that disruption of CD43, CD44, PDPN, and Siglec-1 significantly altered cancer cell susceptibility to NK killing both in vitro and in humanized mouse models. Analysis of clinical datasets show that expression of identified factors correlates with patient survival outcomes in an NK-context dependent manner supporting their therapeutic relevance. Most notably, our mechanistic studies demonstrate that CD43-mediated NK cell resistance operates independently of its previously proposed interaction with Siglec-7 on NK cells. Furthermore, we find that targeting CD43 on either NK cells or engineered T cells substantially enhances their cytotoxic activity against leukemia cell lines. These results establish gain-of-function screening as a powerful approach for discovering immunoregulatory surface proteins and identify multiple promising targets for enhancing NK cell-based cancer immunotherapies.
2026-04-15 | GSE327341 | GEO
Project description:To identify genes that are differentially expressed between CD44+ and CD44- cells in colonospheres, we have employed whole genome microarray expression profiling as a discovery platform. Colonospheres from four colon cancer patients were sorted into CD44+ and CD44- cells using the FACS Aria II Cell Sorter, and total RNA extracted from the cells were labeled with Cy3 and used for microarray analyses with Agilent Whole Human Genome Oligo Microarrays.
2012-12-07 | GSE38706 | GEO
Project description:CD44+/CD24- subpopulation of normal and cancerous breast epithelial cells are suggested to have stem cell properties. The goal of this study was to identify gene expression differences between CD44+/CD24- and CD44-/CD24+ subpopulation of cells from a same cell lines. We selected MCF-10A cells, which are immortalized derived from a fibrocystic breast disease. These cells are immortalized but not transformed and express basal cell markers. Cells were from a single sort but plated into four 100 mm plates. RNA was prepared from each plate separately for the analysis. Comparison of gene expression between 2 groups ( CD44+/CD24- and CD44-/CD24+) 4 replicates each.
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