Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with a poor prognosis due to late diagnosis and loco-regional metastasis. Partial or more complete epithelial–mesenchymal transition (EMT) plays a role in tumor progression; however, it remains a challenge to observe the EMT in vivo, due to its transient nature. Here, we developed a novel catulin promoter-based reporter system that allows us to isolate and characterize in vivo a small fraction of invasive cancer cells. The analyses of tumors revealed that Catulin-green fluorescent protein (GFP)-positive cells were enriched in clusters of cells at the tumor invasion front. A functional genomic study unveiled genes involved in cellular movement and invasion providing a molecular profile of HNSCC invasive cells. This profile overlapped partially with the expression of signature genes related to the partial EMT available from the single cell analysis of human HNSCC specimens, highlighting the relevance of our data to the clinical disease progression state. Interestingly, we also observed upregulations of genes involved in axonal guidance—L1 cell adhesion molecule (L1CAM), neuropilin-1, semaphorins, and ephrins, indicating potential interactions of cancer cells and neuronal components of the stroma. Taken together, our data indicated that the catulin reporter system marked a population of invasive HNSCC cells with a molecular profile associated with cancer invasion.
Highlights
Head and neck carcinomas (HNC) are malignant neoplasms that affect important anatomical structures of the upper digestive tract and respiratory system, such as the tongue, mouth, pharynx, larynx, nasal cavity, sinuses, and salivary glands, and often affect key sensory nerves in the peripheral nervous system
The corresponding squamous cell carcinoma (SCC) cell lines were used as a control, to set up two gates, i.e., green fluorescent protein (GFP)-negative and GFP-positive (gate P2, which cut off 99.9% of the SCC15 cells; Figure 1B(1), Supplementary Figure S2A(1))
The first passage of the SCC15CatGFP plus population contained 50% of GFP-positive cells, and this number dropped with every passage stabilizing at the sixth passage, at the level of 25% of GFP-positive cells
Summary
Head and neck carcinomas (HNC) are malignant neoplasms that affect important anatomical structures of the upper digestive tract and respiratory system, such as the tongue, mouth, pharynx, larynx, nasal cavity, sinuses, and salivary glands, and often affect key sensory nerves in the peripheral nervous system. Head and neck squamous cell carcinoma (HNSCC), which accounts for the majority of HNC cases, is the sixth most common cancer in the world, with a low and unchanged 50% 5-year survival rate [4,5] This poor survival is likely due to the fact that local invasion, lymph node involvement, and metastasis are often present at the time of diagnosis [6]. An important aspect of HNSCC progression is the specific tumor microenvironment (TME), which consists of the extracellular matrix (ECM) as well as resident and recruited cells in the vicinity of cancer These cells include cancer-associated fibroblasts (CAFs), which in the head and neck area are neural-crest-derived, adipose cells, immune-inflammatory cells as well as nerve, blood, and lymphatic vascular networks [7,8]. This cross-talk takes place through paracrine signaling or direct interactions between cells, which leads to bidirectional remodeling, enabling tumor cell proliferation, invasion, and migration followed by metastasis [10]
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