Therapeutic targeting of the TPX2/TTK network in colorectal cancer
<h3>Background</h3><p dir="ltr">While the increased screening, changes in lifestyle, and recent advances in treatment regimen have decreased colorectal cancer (CRC) mortality, metastatic disease and recurrence remains a major clinical challenge. In the era of precision me...
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| مؤلفون آخرون: | , , , , |
| منشور في: |
2023
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| الموضوعات: | |
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إضافة وسم
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| _version_ | 1864513509184765952 |
|---|---|
| author | Hibah Shaath (5599658) |
| author2 | Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Dinesh Velayutham (5444072) Puthen Veettil Jithesh (12040358) Nehad M. Alajez (7397276) |
| author2_role | author author author author author |
| author_facet | Hibah Shaath (5599658) Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Dinesh Velayutham (5444072) Puthen Veettil Jithesh (12040358) Nehad M. Alajez (7397276) |
| author_role | author |
| dc.creator.none.fl_str_mv | Hibah Shaath (5599658) Radhakrishnan Vishnubalaji (3563306) Ramesh Elango (7542068) Dinesh Velayutham (5444072) Puthen Veettil Jithesh (12040358) Nehad M. Alajez (7397276) |
| dc.date.none.fl_str_mv | 2023-09-28T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1186/s12964-023-01290-2 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Therapeutic_targeting_of_the_TPX2_TTK_network_in_colorectal_cancer/26535493 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Colorectal cancer Precision medicine TPX2 TTK DDX39A LRP8 Gene-drug-interaction |
| dc.title.none.fl_str_mv | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">While the increased screening, changes in lifestyle, and recent advances in treatment regimen have decreased colorectal cancer (CRC) mortality, metastatic disease and recurrence remains a major clinical challenge. In the era of precision medicine, the identification of actionable novel therapeutic targets could ultimately offer an alternative treatment strategy for CRC.</p><h3>Methods</h3><p dir="ltr">RNA-Seq was conducted using the illumina platform, while bioinformatics analyses were conducted using CLC genomics workbench and iDEP.951. Colony forming unit, flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. The growth potential of CRC cells under 3-dimensional (3D) conditions was assessed using Matrigel. STRING database (v11.5) and Ingenuity Pathway Analysis (IPA) tool were used for network and pathway analyses. CRISPR-Cas9 perturbational effects database was used to identify potential therapeutic targets for CRC, through integration with gene-drug interaction database. Structural modeling and molecular docking were used to assess the interaction between candidate drugs and their targets.</p><h3>Results</h3><p dir="ltr">In the current study, we investigated the therapeutic potential of targeting TPX<sub>2</sub>, TTK, DDX39A, and LRP8, commonly upregulated genes in CRC identified through differential expression analysis in CRC and adjacent non-cancerous tissue. Targeted depletion of TPX<sub>2</sub> and TTK impaired CRC proliferation, cell cycle progression, and organoid formation under 3D culture conditions, while suppression of DDX39A and LRP8 had modest effects on CRC colony formation. Differential expression analysis and bioinformatics on TPX2 and TTK-deficient cells identified cell cycle regulation as the hallmark associated with loss of TPX<sub>2</sub> and TTK. Elevated expression of TPX<sub>2 </sub>and TTK correlated with an oncogenic state in tumor tissue from patients with colon adenocarcinoma, thus corroborating an oncogenic role for the TPX<sub>2</sub>/TTK network in the pathogenesis of CRC. Gene set enrichment and pathway analysis of TPX2<sup>high</sup>/TTK<sup>high</sup> CRC identified numerous additional gene targets as integral components of the TPX<sub>2</sub>/TTK network. Integration of TPX<sub>2</sub>/TTK enriched network with CRISPR-Cas9 functional screen data identified numerous novel dependencies for CRC. Additionally, gene-drug interaction analysis identified several druggable gene targets enriched in the TPX<sub>2</sub>/TTK network, including AURKA, TOP<sub>2</sub>A, CDK1, BIRC<sub>5</sub>, and many others.</p><h3>Conclusions</h3><p dir="ltr">Our data has implicated an essential role for TPX2 and TTK in CRC pathogenesis and identified numerous potential therapeutic targets and their drug interactions, suggesting their potential clinical use as a novel therapeutic strategy for patients with CRC.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Communication and Signaling<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12964-023-01290-2" target="_blank">https://dx.doi.org/10.1186/s12964-023-01290-2</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_3bef9a2e83666564ec366a21726034a7 |
| identifier_str_mv | 10.1186/s12964-023-01290-2 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26535493 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Therapeutic targeting of the TPX2/TTK network in colorectal cancerHibah Shaath (5599658)Radhakrishnan Vishnubalaji (3563306)Ramesh Elango (7542068)Dinesh Velayutham (5444072)Puthen Veettil Jithesh (12040358)Nehad M. Alajez (7397276)Biomedical and clinical sciencesClinical sciencesOncology and carcinogenesisPharmacology and pharmaceutical sciencesColorectal cancerPrecision medicineTPX2TTKDDX39ALRP8Gene-drug-interaction<h3>Background</h3><p dir="ltr">While the increased screening, changes in lifestyle, and recent advances in treatment regimen have decreased colorectal cancer (CRC) mortality, metastatic disease and recurrence remains a major clinical challenge. In the era of precision medicine, the identification of actionable novel therapeutic targets could ultimately offer an alternative treatment strategy for CRC.</p><h3>Methods</h3><p dir="ltr">RNA-Seq was conducted using the illumina platform, while bioinformatics analyses were conducted using CLC genomics workbench and iDEP.951. Colony forming unit, flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. The growth potential of CRC cells under 3-dimensional (3D) conditions was assessed using Matrigel. STRING database (v11.5) and Ingenuity Pathway Analysis (IPA) tool were used for network and pathway analyses. CRISPR-Cas9 perturbational effects database was used to identify potential therapeutic targets for CRC, through integration with gene-drug interaction database. Structural modeling and molecular docking were used to assess the interaction between candidate drugs and their targets.</p><h3>Results</h3><p dir="ltr">In the current study, we investigated the therapeutic potential of targeting TPX<sub>2</sub>, TTK, DDX39A, and LRP8, commonly upregulated genes in CRC identified through differential expression analysis in CRC and adjacent non-cancerous tissue. Targeted depletion of TPX<sub>2</sub> and TTK impaired CRC proliferation, cell cycle progression, and organoid formation under 3D culture conditions, while suppression of DDX39A and LRP8 had modest effects on CRC colony formation. Differential expression analysis and bioinformatics on TPX2 and TTK-deficient cells identified cell cycle regulation as the hallmark associated with loss of TPX<sub>2</sub> and TTK. Elevated expression of TPX<sub>2 </sub>and TTK correlated with an oncogenic state in tumor tissue from patients with colon adenocarcinoma, thus corroborating an oncogenic role for the TPX<sub>2</sub>/TTK network in the pathogenesis of CRC. Gene set enrichment and pathway analysis of TPX2<sup>high</sup>/TTK<sup>high</sup> CRC identified numerous additional gene targets as integral components of the TPX<sub>2</sub>/TTK network. Integration of TPX<sub>2</sub>/TTK enriched network with CRISPR-Cas9 functional screen data identified numerous novel dependencies for CRC. Additionally, gene-drug interaction analysis identified several druggable gene targets enriched in the TPX<sub>2</sub>/TTK network, including AURKA, TOP<sub>2</sub>A, CDK1, BIRC<sub>5</sub>, and many others.</p><h3>Conclusions</h3><p dir="ltr">Our data has implicated an essential role for TPX2 and TTK in CRC pathogenesis and identified numerous potential therapeutic targets and their drug interactions, suggesting their potential clinical use as a novel therapeutic strategy for patients with CRC.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Communication and Signaling<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1186/s12964-023-01290-2" target="_blank">https://dx.doi.org/10.1186/s12964-023-01290-2</a></p>2023-09-28T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1186/s12964-023-01290-2https://figshare.com/articles/journal_contribution/Therapeutic_targeting_of_the_TPX2_TTK_network_in_colorectal_cancer/26535493CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/265354932023-09-28T09:00:00Z |
| spellingShingle | Therapeutic targeting of the TPX2/TTK network in colorectal cancer Hibah Shaath (5599658) Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Colorectal cancer Precision medicine TPX2 TTK DDX39A LRP8 Gene-drug-interaction |
| status_str | publishedVersion |
| title | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| title_full | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| title_fullStr | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| title_full_unstemmed | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| title_short | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| title_sort | Therapeutic targeting of the TPX2/TTK network in colorectal cancer |
| topic | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences Colorectal cancer Precision medicine TPX2 TTK DDX39A LRP8 Gene-drug-interaction |