CEACAM6 Human

What is CEACAM6 and where is it located in the human genome? (Basic)

CEACAM6 is a cell adhesion protein belonging to the Carcinoembryonic antigen (CEA) family of glycosyl phosphatidyl inositol anchored cell surface glycoproteins. The CEACAM6 gene is located at chromosome 19q13.2 in the human genome. It plays important roles in various biological processes, including cell adhesion, intracellular and intercellular signaling, and tissue architecture formation .

What is the molecular structure of CEACAM6? (Basic)

CEACAM6 consists of:

• An N-terminus Ig-like V-type domain

• Two N-terminus IgC-like domains

• A membrane-linked glycoprotein

The coding region is composed of 6 exons with a single transcript encoding 344 amino acids. The extracellular N-terminus Ig-like V-type domain is crucial for homophilic and heterophilic intercellular adhesion. CEACAM6 is anchored to the cell surface via the transmembrane domain of the membrane-linked glycoproteins .

How does CEACAM6 interact with other molecules despite lacking transmembrane domains? (Advanced)

Though CEACAM6 lacks transmembrane or intracellular structural domains, it affects intracellular signaling through several mechanisms:

• Glycosylation-mediated effects: Glycosylation regulates membrane protein folding, altering receptor activation and changing epitope exposure for antibody recognition.

• Heterodimeric interactions: CEACAM6 can form complexes with other CEACAMs, including:

  • Homodimeric complexes with itself

  • Heterodimeric complexes with CEACAM8 through its Ig-like V-type domain

  • Interactions with CEACAM1 and CEA

• Receptor crosstalk: N-glycosylated CEACAM6 interacts with EGFR in oral squamous cell carcinoma (OSCC) cells, regulating intracellular signaling for tumor invasion, migration, and metastasis .

Which cancers exhibit altered CEACAM6 expression? (Basic)

CEACAM6 is generally upregulated in multiple cancer types, including:

• Pancreatic adenocarcinoma

• Breast cancer

• Non-small cell lung cancer

• Gastric cancer

• Colon cancer

• Colorectal cancer

• Mucinous ovarian cancer

Interestingly, there are exceptions to this pattern. For example, in laryngeal squamous cell carcinoma (LSCC), studies have shown downregulation of CEACAM6 compared to non-cancer controls from the head and neck region .

What explains the contradictory expression patterns of CEACAM6 in different cancer types? (Advanced)

The contradictory expression patterns of CEACAM6 observed in different cancers may be attributed to several factors:

• Tissue-specific regulation: CEACAM6 may have tissue-specific regulatory mechanisms that result in differential expression patterns.

• Genetic alterations: Research on LSCC cell lines examined DNA copy number changes (using a-CGH), promoter DNA methylation status, and occurrence of gene mutations to explain CEACAM6 downregulation.

• Tumor staging and grading correlation: In LSCC, significant gene downregulation was observed specifically in cell lines derived from advanced, high-grade tumors compared to controls, suggesting stage-specific expression patterns.

• Epigenetic mechanisms: DNA methylation of the CEACAM6 promoter region may contribute to transcriptional silencing in certain cancer types .

This contradictory expression pattern highlights the importance of context-specific research when studying CEACAM6 as a potential biomarker or therapeutic target.

What are the key signaling pathways influenced by CEACAM6? (Basic)

CEACAM6 influences several critical signaling pathways that promote cancer progression:

• PI3K/AKT pathway: CEACAM6 increases phosphorylated AKT levels, which is involved in the progression of various human tumors. This pathway can be inhibited by LY294002, a PI3K inhibitor, which reverses CEACAM6-induced EMT via mesenchymal-epithelial transition.

• ERK1/2/MAPK pathway: CEACAM6 activates this pathway either directly or through EGFR.

• SRC/focal adhesion kinase/PI3K/AKT pathway: Activation leads to stimulation of tumor proliferation, invasion, migration, resistance to anoikis and chemotherapy, as well as angiogenesis.

• Cell cycle regulation: CEACAM6 promotes tumor proliferation by increasing levels of cyclin D1 and cyclin-dependent kinase 4 proteins .

How does CEACAM6 contribute to epithelial-mesenchymal transition (EMT) in gastric cancer? (Advanced)

CEACAM6 plays a significant role in promoting EMT in gastric cancer through multiple mechanisms:

• EMT marker modulation: Forced CEACAM6 expression in gastric cancer cells (MKN-45, SGC-7901) increased EMT markers including:

  • N-cadherin, vimentin, and Slug (increased)

  • E-cadherin (decreased)

• Transcriptional regulation: CEACAM6 affects the Snail family of zinc finger transcription factors, including Snail and Slug, which are critical for EMT. Slug was first described as a transcription factor expressed in cells undergoing EMT during gastrulation and neural crest emergence.

• AKT signaling: CEACAM6 increases levels of phosphorylated AKT, which is involved in cancer progression. LY294002, a PI3K inhibitor, can reverse CEACAM6-induced EMT via mesenchymal-epithelial transition.

• Clinical correlations: E-cadherin expression was negatively associated with the depth of tumor invasion, lymph node metastasis, and TNM stage in gastric cancer tissues, linking CEACAM6-mediated EMT to clinical outcomes .

What techniques are commonly used to analyze CEACAM6 expression? (Basic)

Several techniques are utilized to analyze CEACAM6 expression in research settings:

• Expression microarrays: Used to identify differential expression between cancer samples and non-cancer controls.

• Quantitative PCR (RT-qPCR): Employed to validate and quantify changes in CEACAM6 expression. This method can be correlated with clinical parameters such as tumor staging (TNM) and grading (G).

• Array-based comparative genomic hybridization (a-CGH): Utilized to analyze DNA copy number status using platforms such as Human Genome CGH 244K or 44K Microarrays. Copy number alterations are identified by evaluating the mean log2ratio for chromosomal regions harboring CEACAM6.

• Promoter DNA methylation analysis: Used to investigate epigenetic regulation of CEACAM6 expression .

How can researchers investigate mechanisms responsible for CEACAM6 deregulation? (Advanced)

To investigate the mechanisms responsible for CEACAM6 deregulation, researchers can implement a multi-faceted approach:

• DNA copy number analysis:

  • Employ array-based comparative genomic hybridization (a-CGH)

  • Determine gene position according to genome browsers (e.g., UCSC Genome Browser database)

  • Evaluate mean log2ratio for chromosomal regions harboring CEACAM6

  • Consider normal range between +0.5 and -0.5, with values below -0.5 recognized as potential deletions

• Mutation screening:

  • Utilize databases like cBioPortal and COSMIC to identify inactivating mutations

  • Screen large sample sets (e.g., the dataset from cBioPortal included 279 HNSCC cases)

  • Focus on specific cancer subtypes (e.g., COSMIC database included 908 HNSCC cases, with 26 derived from larynx)

• Epigenetic analysis:

  • Examine promoter methylation status

  • Correlate methylation patterns with expression levels

  • Investigate the role of transcriptional repressors

• Transcriptional regulation analysis:

  • Study the role of microRNAs (miR-146, miR-26a, miR-29a/b/c, miR-128, miR-1256)

  • Investigate the CD151/TGF-β1/Smad3 axis

  • Analyze DNA methylation patterns affecting transcription .

What therapeutic approaches target CEACAM6 in cancer? (Basic)

Multiple therapeutic approaches targeting CEACAM6 have been developed:

• Monoclonal antibodies:

  • Humanized monoclonal antibody NEO-201, which targets CEACAM6, shows specificity for various cancers including colon, pancreatic, and mucinous ovarian cancer

  • Anti-CEACAM6 single domain antibody (sdAb) demonstrates anti-tumor effects in pancreatic adenocarcinoma cell models

• Optimized antibody formats:

  • Heavy chain antibody 2A3-mFc shows superior tumor detection and pharmacokinetics compared to single domain and full-length antibodies

  • Multivalent antibodies, including bivalent sdAb and quadrivalent sdAb anti-CEACAM6, demonstrate higher affinity and therapeutic efficacy

• Nanoparticle-based delivery:

  • CEACAM6-targeting albumin-based nanoparticles for drug delivery to metastatic anoikis-resistant tumor cells

  • Polyethylene glycol-modified iron oxide nanoparticles with triple single chain antibodies for diagnosis and treatment of pancreatic adenocarcinoma

• RNA interference:

  • Delivery of siCEACAM6 using pH low insertion peptide shows therapeutic potential in lung adenocarcinoma models .

How do anti-CEACAM6 therapies address anoikis resistance in cancer? (Advanced)

Anoikis resistance (resistance to apoptosis induced by inadequate or inappropriate adhesion to substrate) is a key mechanism in cancer metastasis, and CEACAM6 plays a significant role in this process:

• CEACAM6 expression in anoikis-resistant cells:

  • CEACAM6 is highly expressed in metastatic anoikis-resistant tumor cells

  • This overexpression contributes to survival in circulation during metastasis

• Antibody-mediated reversal of anoikis resistance:

  • Treatment with anti-CEACAM6 monoclonal antibody clone 8F5 decreases cellular CEACAM6 expression in A549 cells

  • This treatment effectively reverses anoikis resistance, potentially limiting metastatic potential

• Targeted drug delivery to anoikis-resistant cells:

  • Human serum albumin nanomedicine targeting CEACAM6 can deliver encapsulated chemotherapeutic drugs (e.g., adriamycin)

  • This approach effectively targets circulating metastatic anoikis-resistant tumor cells

  • Based on CEACAM6 expression in various tumors, this strategy may target multiple types of metastatic tumor cells .

What clinical trials are investigating CEACAM6-targeted therapies? (Basic)

Clinical trials are underway to evaluate CEACAM6-targeted therapies:

A Phase 1, first-in-human, dose escalation and expansion study (Bayer Identifier: 18650, ClinicalTrials.gov Identifier: NCT03596372) is investigating BAY1834942, an anti-CEACAM6 antibody. The study aims to:

• Assess safety, tolerability, pharmacokinetics, pharmacodynamics, and tumor response profile of BAY1834942

• Target patients with advanced solid tumors known to have a prevalence for CEACAM6 expression

• Include both dose escalation and tumor type-specific expansion phases

Key inclusion criteria for this trial include:

• Male or female patients aged ≥18 years

• Histologically confirmed advanced/metastatic solid tumors expressing CEACAM6

• Dose escalation phase: includes gastric/GEJ cancer, esophageal cancer, NSCLC, CRC, pancreatic cancer, cervical cancer, breast cancer, bladder cancer, head and neck squamous cell cancer, and bile duct cancer

• Dose expansion phase: focuses on advanced adeno NSCLC, CRC, and gastric/GEJ adenocarcinoma

• ECOG-PS of 0 to 1

• Adequate organ function (bone marrow, liver, kidneys)

• Adequate coagulation and cardiac function .

What are the methodological approaches for assessing CEACAM6 as a blood biomarker? (Advanced)

The evaluation of CEACAM6 as a blood biomarker requires systematic methodological approaches:

• Collective omics data (COD) training curriculum:

  • Structured retrieval and aggregation of gene-specific data

  • Comprehensive gathering and synthesis of relevant information from both literature and transcriptome datasets

• Literature profiling:

  • Identification of major diseases associated with CEACAM6

  • Establishment of its relevance as a biomarker across different conditions

• Transcriptome dataset analysis:

  • Access to blood transcriptome datasets to identify additional instances where CEACAM6 transcript levels differ between cases and controls

  • Integration of transcript abundance data with clinical parameters

• Information structuring and visualization:

  • Capture of retrieved information in a structured format

  • Aggregation in interactive circle packing plots for comprehensive data visualization and interpretation

This systematic approach allows researchers to determine whether CEACAM6 should be included in targeted panels for clinical applications, particularly when selecting from genome-wide scale measurements to smaller, clinically relevant gene sets .

What are the key gaps in CEACAM6 research that need to be addressed? (Basic)

Several important research gaps exist in our understanding of CEACAM6:

• Contradictory expression patterns: Further investigation is needed to understand why CEACAM6 is upregulated in most cancers but downregulated in others (e.g., laryngeal squamous cell carcinoma).

• Contextual function: More research is required to understand how the same molecule can function as both an oncogene and a potential tumor suppressor depending on the cellular context.

• Predictive biomarker validation: Larger clinical studies are needed to validate CEACAM6 as a predictive biomarker for treatment response, particularly for targeted therapies.

• Resistance mechanisms: Studies should investigate mechanisms of resistance to CEACAM6-targeted therapies to develop more effective treatment strategies.

• Normal physiological roles: Greater understanding of CEACAM6's functions in normal tissues could improve therapeutic targeting with reduced side effects .

What are emerging advanced approaches for studying CEACAM6 in cancer research? (Advanced)

Several advanced approaches are emerging for studying CEACAM6 in cancer research:

• Multimodal single-cell analyses:

  • Integration of transcriptomics, proteomics, and epigenomics at the single-cell level

  • Investigation of CEACAM6 heterogeneity within tumors and its impact on treatment response

• Improved therapeutic antibody design:

  • Development of bispecific antibodies targeting CEACAM6 and immune checkpoint molecules

  • Engineering antibodies with enhanced tumor penetration and reduced immunogenicity

• Advanced nanoparticle delivery systems:

  • Creation of nanoparticles with improved targeting specificity and reduced off-target effects

  • Development of dual-targeting nanoparticles for CEACAM6-expressing tumors

• Combination therapy approaches:

  • Identification of synergistic combinations of CEACAM6-targeted therapies with conventional treatments

  • Optimization of dosing schedules to maximize efficacy and minimize toxicity

• Clinical validation on large sample sizes:

  • Conduct of large-scale clinical studies across multiple cancer types

  • Implementation of standardized CEACAM6 assessment methods to enable cross-study comparisons

These advanced approaches will help address the gaps in our understanding of CEACAM6 and potentially lead to improved diagnostic and therapeutic strategies for CEACAM6-expressing cancers .