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The fibrosis-targeted collagen/integrins gene profile predicts risk of metastasis in pulmonary neuroendocrine neoplasms

ABSTRACT: In this study, we sought to identify differentially expressed collagen/integrin genes in PNENs in order to understand the molecular mechanisms underlying the development of stroma-associated fibrosis for invasion and metastasis. We compared collagen/integrin gene expression profiling between PNE tumors (PNETs) and PNE carcinomas (PNECs) using a two-stage design. First, we used PCR Array System for 84 ECM-related genes, and among them, we found COL1A2, COL3A1, COL5A2, ITGA5, ITGAV, and ITGB1 functionally involved in the formation of the stroma-associated fibrosis among PNENs histological subtypes. Second, we examined the clinical association between the six collagen/integrin genes in tumor tissues from 24 patients with surgically excised PNENs.However, the pathological exam of their resected tissues demonstrated that 10 developed lymph node metastasis and 7 distant metastasis. We demonstrated and validated up regulation of the six fibrogenic genes in PNECs and down regulation in PNETs that were significantly associated with metastasis-free and overall survival (P<0.05). Our study implicates up regulation of fibrogenic genes as a critical molecular event leading to lymph node and distant metastasis in PNENs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181381 | GEO | 2021/08/04

REPOSITORIES: GEO

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Project description:Lymph node metastasis is a poor prognosis indicator in esophageal cancer. Although tumor spreading currently forms the main basis for therapy selection, the molecular mechanisms underlying the metastatic pathway remain insufficiently understood. Several studies aimed to investigate these mechanisms but focused mainly on regulatory patterns in the tumors themselves and/or the invaded lymph nodes. To date no study has yet investigated the potential changes on transcription level, which take place within the yet non-invaded niche. Here we provide a comprehensive description of these regulations in patients. In this study the transcriptomic profiles of regional lymph nodes were determined for two patient groups: patients classified as pN1 (metastasis) or pN0 (no metastasis) respectively. All investigated lymph nodes, also those from pN1 patients, were still free of metastasis. The gene expression data was obtained via microarray analysis. Top candidates were validated via PCR and immunohistochemistry. The results show that regional lymph nodes of pN1 patients differ decisively from those of pN0 patients – even before metastasis has taken place. In the pN0 group distinct immune response patterns were observed. In contrast, lymph nodes of the pN1 group exhibited a clear profile of reduced immune response and reduced proliferation, but increased apoptosis, enhanced hypoplasia and morphological conversion processes. DKK1 was the most significant gene associated with the molecular mechanisms taking place in lymph nodes of patients suffering from metastasis (pN1). We assume that the two molecular profiles observed constitute two different stages of a progressive disease. Finally we suggest that DKK1 might play an important role within the mechanisms leading to lymph node metastasis. First, samples were classified according to the principal status of the patients exhibiting (pN1 group) or non-exhibiting (pN0 group) metastasis in regional lymph nodes. The comparison of pN1 and pN0 patients should highlight the general differences in regulations that might lead to or prevent from metastasis. Second, two lymph node samples were collected from each patient, one node located close to the tumor (regional) and the second node distant to the tumor. While the distant nodes served as reference sample the regional nodes were investigated for transcriptional regulations. Key to the work presented here is that all nodes investigated were made sure to be still metastasis free, independent of the patients’ pN1/pN0 classification and of the location relative to the tumor. This should allow the identification of early changes occurring prior to metastasis homing.

Project description:Head and neck squamous cell carcinoma (HNSCC) often present with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently immunotherapy for metastatic, or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and efficacy at controlling occult distant sites remains poor. Whilst our understanding of the tumour microenvironment, conducive for effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort, to understand the expression of proteins within tumour, and stromal compartments of the respective sites in both matched and unmatched patients’ samples. In unmatched analyses of n=43 primary and 11 nodal metastasis, our data indicated that tumour cells in nodal metastases had higher levels of Ki-67, PARP, BAD and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair and apoptosis within these metastatic cells. Conversely, in matched analyses (n=7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumours. Univariate, overall survival (OS) analysis indicated CD25 in tumour regions of primary tumours to be associated with reduced survival (HR=3.3, p=0.003), while partial response (PR) was associated with an improved OS (HR=0.33, p=0.015). This study highlights the utility of spatial proteomics for delineating tumour and stroma compartment composition, and the utility towards understanding these properties in locoregional metastasis. These findings indicate the unique biological properties of lymph node metastases that may elucidate further understanding of the subsequent distant metastatic potential of OPSCC. In this dataset, we applied GeoMx DSP protein profiling to tumour and tumour microenvironment regions of primary and lymphnode metastasis FFPE samples. The files here represent the Ncounter readout from this assay.

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The fibrosis-targeted collagen/integrins gene profile predicts risk of metastasis in pulmonary neuroendocrine neoplasms

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