Pulmonary Neuroendocrine Neoplasms Overexpressing Epithelial-Mesenchymal Transition Mechanical Barriers Genes Lack Immune-Suppressive Response and Present an Increased Risk of Metastasis

Abstract

Typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC), and small cell lung carcinomas (SCLC) encompass a bimodal spectrum of metastatic tumors with morphological, histological and histogenesis differences, The hierarchical structure reveals high cohesiveness between neoplastic cells by mechanical desmosomes barrier assembly in carcinoid tumors and LCNEC, while SCLC does not present an organoid arrangement in morphology, the neoplastic cells are less cohesive. However, the molecular mechanisms that lead to PNENs metastasis remain largely unknown and require further study. In this work, epithelial to mesenchymal transition (EMT) transcription factors were evaluated using a set of twenty-four patients with surgically resected PNENs, including carcinomas. Twelve EMT transcription factors (BMP1, BMP7, CALD1, CDH1, COL3A1, COL5A2, EGFR, ERBB3, PLEK2, SNAI2, STEAP1, and TCF4) proved to be highly expressed among carcinomas and downregulated in carcinoid tumors, whereas upregulation of BMP1, CDH2, KRT14 and downregulation of CAV2, DSC2, IL1RN occurred in both histological subtypes. These EMT transcription factors identified were involved in proliferative signals, epithelium desmosomes assembly, and cell motility sequential steps that support PNENs invasion and metastasis in localized surgically resected primary tumor. We used a two-stage design where we first examined the candidate EMT transcription factors using a whole-genome screen, and subsequently, confirmed EMT-like changes by transmission electron microscopy and then, the EMT-related genes that were differentially expressed among PNENs subtypes were predicted through a Metascape analysis by in silico approach. A high expression of these EMT transcription factors was significantly associated with lymph node and distant metastasis. The sequential steps for invasion and metastasis were completed by an inverse association between functional barrier created by PD-L1 immunosuppressive molecule and EMT transcriptional factors. Our study implicates upregulation of EMT transcription factors to high proliferation rates, mechanical molecular barriers disassembly and increased cancer cell motility, as a critical molecular event leading to metastasis risk in PNENs thus emerging as a promising tool to select and customize therapy.

Proposing Specific Neuronal Epithelial-to-Mesenchymal Transition Genes as an Ancillary Tool for Differential Diagnosis among Pulmonary Neuroendocrine Neoplasms

“…The tumor samples were enriched for earlier stages (I/II) in carcinoid tumors according to the 8th edition of the International Union for Cancer Control (UICC) TNM Classification of Malignant Tumors [ 1 ] and consisted of primary lung tumors obtained by surgical resection. The TC and AC cases were selected to obtain a balanced number of cases in each group, as in our previous study [ 12 ]. The cohort comprises 5 TC, 5 AC, 4 LCNEC, and 10 SCLC according to the current World Health Organization (WHO) 2021 classification [ 2 ].…”

“…Ct_HKG)]. The studied genes that were differently expressed (DEG) were obtained from a panel of 84 EMT genes, the same platform that was applied in a previous study by our group (GSE181381) [ 12 ].…”

“…In this context, additional markers also applicable to biopsy specimens, which correlate PNENs subtypes with systemic treatment response, are much needed, and current potential candidates are neurogenic EMT genes. Previously, using cDNA microarrays, we evaluated the expression profile of 17 EMT-related genes among PNENs histological types, expressing different levels of ( BMP1 , BMP7 , CALD1 , CDH1 , COL3A1 , COL5A2 , EGFR , ERBB3, PLEK2 , SNAI2 , STEAP1 , TCF4 , CDH2 , KRT14 , CAV2 , DSC2 , and IL1RN ) and which were also related to mechanical barriers [ 12 ]. These results prompted us to examine whether a classification of PNENs according to EMT molecular subtyping, in conjunction with classical morphologic characteristics, may provide a clinically relevant solution.…”

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis

“…It could be assumed that STEAP1 may play a similar role in PI3K-Akt signaling pathway. Acting as EMT transcription factors, EGFR and STEAP1 were proved to be highly expressed among pulmonary neuroendocrine carcinomas and downregulated in carcinoid tumors [ 44 ], which suggested that STEAP1 may have interaction with EGFR pathway in the process of EMT. However, there are few studies about STEAP1 and HGFR or integrin-mediated signaling pathway.…”

An Analysis of BMP1 Associated with m6A Modification and Immune Infiltration in Pancancer

“…A recent study implicated the upregulation of EMT transcription factors (BMP1, CDH2, KRT14, etc.) to high proliferation rates, mechanical molecular barriers disassembly, and increased cancer cell motility, leading to metastasis risk in pulmonary neuroendocrine neoplasms [ 15 ]. BMP1 is a potential biomarker and mediator in diversified malignant tumors, whereas the function and pathway of its impact on pancancer remain unclear.…”