Integrated transcriptomics and proteomics data analysis identifies CDH17 as a key cell surface target in colorectal cancer

Wong, Kah Keng

doi:10.1016/j.compbiolchem.2023.107897

Cited by 5 publications

(5 citation statements)

References 121 publications

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“…CDH17 expression has been demonstrated in CRC human samples and can be used along with other markers, such as mucin 2 (MUC2) and cyclooxygenase-2 (COX-2), to predict disease progression and prognosis in CRC patients [ 18 , 21 ]. To further confirm the expression of CDH17 in CRC, the RNA expression of CDH17 in colon adenocarcinoma (COAD) tissues was examined using data from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, high expression of CDH17 protein has also been observed in lung cancers [ 17 ]. CDH17 has become a popular target due to its frequent membrane surface expression on cancer cells and minimal expression in normal tissues [ 14 , 18 ]. A variety of therapeutic and imaging modalities targeting CDH17, such as monoclonal antibodies and their conjugates, as well as chimeric antigen receptor T (CAR-T) cell therapy, have been developed and tested in different preclinical settings [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer

Ding,

Zhou,

Shi

et al. 2024

Biomater Res

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Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer

Ding,

Zhou,

Shi

et al. 2024

Biomater Res

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“…In this in silico study, through a sequence of impartial shortlisting and ranking methodologies, TM4SF4 was shortlisted and finally selected as an optimal cell surface therapeutic target for HCCs. Similar framework had previously been devised and implemented in other types of cancers, including colorectal cancer and diffuse large B cell lymphoma, to identify key cell surface targets in these malignancies [57], and transcriptomics as well as proteomics datasets have regularly been utilized to build algorithms for uncovering crucial biomarkers in cancers [87, 88]. TM4SF4 is not expressed in the critical tissues for survival including the brain, lung, heart and kidney tissues, while overexpressed in HCCs compared with matched and adjacent NTL cells.…”

Section: Discussionmentioning

confidence: 99%

“…The following workflow for shortlisting and ranking procedures have previously been published [57] and adopted here for HCC with modifications. Within the longlist of 12,948 genes expressed in liver cancers defined by HPA, the following sequential shortlisting steps were conducted: (i) Shortlisting for genes not expressed in normal human brain tissues: This is required as cellular immunotherapy such as the approved anti-CD19 CAR T cells have been demonstrated to cause on-target, off-tumor neurotoxicity due to the presence of CD19 expression in brain tissues [58–60].…”

Section: Methodsmentioning

confidence: 99%

Multiomics data analysis identifies TM4SF4 as a cell surface target in hepatocellular carcinoma

Wong,

Ab. Hamid

2024

Preprint

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The clinical application of cellular immunotherapy in hepatocellular carcinoma (HCC) is impeded by the lack of a cell surface target frequently expressed in HCC cells and with minimal presence in normal tissues to reduce on-target, off-tumor toxicity. In thisin silicoanalysis, a longlist of genes (n=12,948) expressed in HCCs according to The Human Protein Atlas database were examined. The aim was to identify the optimal cell surface target, without being shed into circulation, in HCCs and with restrictive expression profile in other normal human tissues. A total of eight genes were shortlisted and they were subsequently ranked according to the combination of their transcript and protein expression levels in HCC cases (n=791) derived from four independent datasets (TCGA, CNHPP, GSE14520, and CHCC). TM4SF4 was the top-ranked target with the highest expression in HCCs. TM4SF4 demonstrated more favorable expression profile with significantly lower expression in normal human tissues but more highly expressed in HCC cases compared with seven other common HCC therapeutic targets. Furthermore, scRNA-seq (GSE149614 and GSE134355) and immunohistochemistry (HPA) datasets showed that TM4SF4 was absent in immune cell populations but highly expressed in the bile duct canaliculi of hepatocytes, a region that is inaccessible to immune cells. In scRNA-seq dataset of HCCs (GSE149614),TM4SF4expression was positively associated with mitochondrial components and oxidative phosphorylation Gene Ontologies in HCC cells (n=15,787 cells), suggesting its potential roles in mitochondrial-mediated oncogenic effects in HCC. Taken together, TM4SF4 is proposed as a promising cell surface target in HCC.

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“…However, the published analyses of DepMap CRISPR screen data have mostly been conducted on a pan‐cancer basis and offer limited guidance for pursuing therapeutic vulnerabilities and predictive biomarkers specific to individual cancer types. Furthermore, analyses of individual cancer types in DepMap to date have narrowly focused on features distinguishing a malignancy of interest from the pan cancer dataset [ 7 , 8 , 9 ], predetermined biological processes [ 10 , 11 , 12 , 13 ], or developing prognostic models [ 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

A novel pipeline for prioritizing cancer type‐specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas

Sannigrahi,

Cao,

Rajagopalan

et al. 2023

Molecular Oncology

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There is limited guidance on exploiting the genome‐wide loss‐of‐function CRISPR screens in cancer Dependency Map (DepMap) to identify new targets for individual cancer types. This study integrated multiple tools to filter these data in order to seek new therapeutic targets specific to head and neck squamous cell carcinoma (HNSCC). The resulting pipeline prioritized 143 targetable dependencies that represented both well‐studied targets and emerging target classes like mitochondrial carriers and RNA‐binding proteins. In total, 14 targets had clinical inhibitors used for other cancers or nonmalignant diseases that hold near‐term potential to repurpose for HNSCC therapy. Comparing inhibitor response data that were publicly available for 13 prioritized targets between the cell lines with high vs. low dependency on each target uncovered novel therapeutic potential for the PAK2 serine/threonine kinase. PAK2 gene dependency was found to be associated with wild‐type p53, low PAK2 mRNA, and diploid status of the 3q amplicon containing PAK2. These findings establish a generalizable pipeline to prioritize clinically relevant targets for individual cancer types using DepMap. Its application to HNSCC highlights novel relevance for PAK2 inhibition and identifies biomarkers of PAK2 inhibitor response.

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Integrated transcriptomics and proteomics data analysis identifies CDH17 as a key cell surface target in colorectal cancer

Cited by 5 publications

References 121 publications

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer

Multiomics data analysis identifies TM4SF4 as a cell surface target in hepatocellular carcinoma

A novel pipeline for prioritizing cancer type‐specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas

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