Abstract
Intra-tumor heterogeneity results from both genetic heterogeneity of cancer (sub)clones and phenotypic plasticity of cancer cells that could be induced by different local microenvironments. Here, we used mass spectrometry imaging (MSI) to compare molecular profiles of primary tumors located in the thyroid gland and their synchronous metastases in regional lymph nodes to analyze phenotypic heterogeneity in papillary thyroid cancer. Two types of cancerous (primary tumor and metastasis) and two types of not cancerous (thyroid gland and lymph node) regions of interest (ROIs) were delineated in postoperative material from 11 patients, then the distribution of tryptic peptides (spectral components) was analyzed by MSI in all tissue regions. Moreover, tryptic peptides identified by shotgun proteomics in corresponding tissue lysates were matched to components detected by MSI to enable their hypothetical protein annotation. Unsupervised segmentation of all cancer ROIs revealed that different clusters dominated in tumor ROIs and metastasis ROIs. The intra-patient similarity between thyroid and tumor ROIs was higher than the intra-patient similarity between tumor and metastasis ROIs. Moreover, the similarity between tumor and its metastasis from the same patients was lower than similarities among tumors and among metastases from different patients (inter-patient similarity was higher for metastasis ROIs than for tumor ROIs). Components differentiating between tumor and its metastases were annotated as proteins involved in the organization of the cytoskeleton and chromatin, as well as proteins involved in immunity-related functions. We concluded that phenotypical heterogeneity between primary tumor and lymph node metastases from the same patient was higher than inter-tumor heterogeneity between primary tumors from different patients.
Highlights
Tumor heterogeneity is a crucial phenomenon involved in the natural history of cancer affecting the response to treatment
Cancer and not cancer regions of interest (ROIs) were delineated by a pathologist in specimens of thyroid glands and lymph nodes derived from 11 patients with papillary thyroid cancer
Spectra generated by imaging of tryptic peptides were exported from both types of cancer ROIs—primary tumors in the thyroid gland and their metastases in lymph nodes, and both types of not cancer ROIs—normal thyroid glands and normal lymph
Summary
Tumor heterogeneity is a crucial phenomenon involved in the natural history of cancer affecting the response to treatment. Though general conclusiveness of experimental evidence is rather limited, the available data on genetic and molecular similarities between a primary tumor and distant metastases could support either possibility [5,6,7,8]. It is still a matter of debate whether cancer cells first form metastases in (regional) lymph nodes subsequently disseminate further (possibly after acquiring additional features), or simultaneously spread from a primary tumor to regional lymph nodes and distant sites. Data on molecular heterogeneity between a primary tumor and cancer cells present in lymph nodes are rather incomplete, which restricts their general impact
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