Integrin α11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells

Zhu, Chang-Qi; Popova, Svetlana N.; Brown, Ewan; Baršytė-Lovejoy, Dalia; Navab, Roya; Shih, Warren; Li, Ming; Lu, Ming; Jurišica, Igor; Penn, Linda Z.; Gullberg, Donald; Tsao, Ming‐Sound

doi:10.1073/pnas.0703040104

Cited by 142 publications

(135 citation statements)

References 45 publications

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“…One of the 14 genes shared between differentially expressed genes in CAFs vs. NFs and NSCLC stroma vs. normal lung tissue is integrin α11 (ITGA11), the protein product of which we reported previously as expressed mainly by tumor stromal fibroblasts with significant influence on the growth of NSCLC cells in vivo (27). ITGA11, together with other differentially expressed genes, including CTHRC1, SULF1, MFAP5, CLU, and THBS2, are known to be regulated by the TGF-β1 signaling pathway (18,19), central to CAF differentiation and epithelial mesenchymal transition (28).…”

Section: Discussionmentioning

confidence: 99%

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Navab

Strumpf

Bandarchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The tumor microenvironment strongly influences cancer development, progression, and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene-expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-β signaling pathway. We have identified a subset of 11 genes (13 probe sets) that formed a prognostic gene-expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene-expression changes revealed prominent involvement of the focal adhesion and MAPK signaling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture-microdissected corresponding primary tumor stroma compared with the matched normal lung. Six of these 14 genes could be induced by TGF-β1 in NF. The results establish the prognostic impact of CAF-associated gene-expression changes in NSCLC patients.integrin α11 | NAViGaTOR | adenocarcinoma | extracellular matrix

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Section: Discussionmentioning

confidence: 99%

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Navab

Strumpf

Bandarchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

321

302

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“…One downregulated gene was Integrin α11 (ITGα11), overexpressed in more than 80% of non-small cell lung cancer cases. 25 Integrins mediate cell-matrix interactions, stimulate signal transduction, and contribute to cancer cell proliferation, motility and survival. 25 Remarkably, miR-373 overexpression significantly reduced ITGα11 mRNA (Supplementary Figure S4B).…”

Section: 'Aza+tsa+cismentioning

confidence: 99%

“…25 Integrins mediate cell-matrix interactions, stimulate signal transduction, and contribute to cancer cell proliferation, motility and survival. 25 Remarkably, miR-373 overexpression significantly reduced ITGα11 mRNA (Supplementary Figure S4B). Hence, ITGα11 mRNA may be a direct miR-373 target.…”

Section: 'Aza+tsa+cismentioning

confidence: 99%

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

et al. 2015

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MicroRNAs (miRs) regulate a variety of cellular processes, and their impaired expression is involved in cancer. Silencing of tumorsuppressive miRs in cancer can occur through epigenetic modifications, including DNA methylation and histone deacetylation. We performed comparative miR profiling on cultured lung cancer cells before and after treatment with 5′aza-deoxycytidine plus Trichostatin A to reverse DNA methylation and histone deacetylation, respectively. Several tens of miRs were strongly induced by such 'epigenetic therapy'. Two representatives, miR-512-5p (miR-512) and miR-373, were selected for further analysis. Both miRs were secreted in exosomes. Re-expression of both miRs augmented cisplatin-induced apoptosis and inhibited cell migration; miR-512 also reduced cell proliferation. TEAD4 mRNA was confirmed as a direct target of miR-512; likewise, miR-373 was found to target RelA and PIK3CA mRNA directly. Our results imply that miR-512 and miR-373 exert cell-autonomous and non-autonomous tumor-suppressive effects in lung cancer cells, where their re-expression may benefit epigenetic cancer therapy.

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“…1 Based on the hypothesized role of integrin α11 in disease, we generated a panel of antibodies to the receptor by cell-based panning of a phage library and identified a lead candidate with high affinity and function modulating activity, but poor biophysical properties.…”

Section: Introductionmentioning

confidence: 99%

Homology modeling and structure-based design improve hydrophobic interaction chromatography behavior of integrin binding antibodies

Jetha

Thorsteinson²,

Jmeian

et al. 2018

mAbs

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Monoclonal antibody (mAb) candidates from high-throughput screening or binding affinity optimization often contain mutations leading to liabilities for further development of the antibody, such as aggregation-prone regions and lack of solubility. In this work, we optimized a candidate integrin α11-binding mAb for developability using molecular modeling, rational design, and hydrophobic interaction chromatography (HIC). A homology model of the parental mAb Fv region was built, and this revealed hydrophobic patches on the surface of the complementarity-determining region loops. A series of 97 variants of the residues primarily responsible for the hydrophobic patches were expressed and their HIC retention times (RT) were measured. As intended, many of the computationally designed variants reduced the HIC RT compared to the parental mAb, and mutating residues that contributed most to hydrophobic patches had the greatest effect on HIC RT. A retrospective analysis was then performed where 3-dimentional protein property descriptors were evaluated for their ability to predict HIC RT using the current series of mAbs. The same descriptors were used to train a simple multi-parameter protein quantitative structure-property relationship model on this data, producing an improved correlation. We also extended this analysis to recently published HIC data for 137 clinical mAb candidates as well as 31 adnectin variants, and found that the surface area of hydrophobic patches averaged over a molecular dynamics sample consistently correlated to the experimental data across a diverse set of biotherapeutics.

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Integrin α11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells

Cited by 142 publications

References 45 publications

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer

Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth

Homology modeling and structure-based design improve hydrophobic interaction chromatography behavior of integrin binding antibodies

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