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Subtype specific analyses reveal Infiltrative Basal Cell Carcinoma are highly interactive with their environment

ABSTRACT: Little is known regarding the differences between BCC subtypes, despite clearly distinct phenotypes and clinical outcomes. In particular, what distinguishes the aggressive infiltrative BCC subtype. We determine that infiltrative BCC do not contain an obviously distinct genomic variant profile however show clear molecular signalling differences compared to less aggressive subtypes. RNA sequencing enabled identification of candidate regulators of infiltrative subtype development such as Wnt and Integrin signalling, and suggested that infiltrative BCC have a strong relationship with their surrounding environment. In particular, WISP1 and Periostin gene expression is associated with the infiltrating subtype and represent candidate regulators of subtype differences in human BCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156171 | GEO | 2021/04/19

REPOSITORIES: GEO

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Project description:Background: Vulvar squamous cell carcinoma (vSCC) is a rare but debilitating disease. One vSCC subtype comprises tumor cells that grow and expand as a cohesive sheet of cells that “pushes” and compresses the associated lymphoplasmacytic (LPC) stroma. Another vSCC subtype features tumor cells that grow in loose association with other tumor cells and infiltrate the associated fibromyxoid (FMX) stroma consisting mainly of extracellular matrix. Clinically, infiltrative vSCC with FMX stroma (Inf/FMX) is significantly associated with lymph node metastases and recurrence. Methods: An unbiased proteomic approach was used to identify pathways that could produce these different vSCC subtypes. Formalin-fixed and paraffin-embedded tissues from 10 cases of pushing vSCC with LPC stroma (Push/LPC) and 8 cases of Inf/FMX were subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Analysis identified 2,265 different proteins in the 18 samples of vSCC. Of these, 344 proteins were differentially expressed (p<0.05) by at least 4-fold between vSCC subtypes. Of these, 59 were higher and 285 lower in Inf/FMX compared to Push/LPC tumors. Consistent with the desmoplastic morphology and increased picrosirius red staining, expression of subunits of several collagens (Col 1, 3, 6, 14, 18) was higher in the more aggressive Inf/FMX tumors. In contrast, signal transducer and activator of transcription 1 (STAT1), an important regulator of several inflammatory pathways, was expressed at lower levels in the Inf/FMX tumors. This finding was confirmed by immunohistochemistry using an antibody to STAT1. An informatics analysis of the differing profiles identified differences in the integrin signaling pathway and inflammation mediated by chemokine and cytokine signaling pathway. This analysis also linked decreased expression of proteins involved antigen processing and presentation and increased expression of those with cell-matrix adhesion as processes with the more aggressive Inf/FMX vSCC subtype. Conclusions: Comparing the proteomic profiles of vSCC morphologic subtypes indicates that increased expression of collagen subunits and decreased expression of STAT1 are associated with a more aggressive tumor subtype. Informatic analyses further identify alterations in cell interaction with matrix and immune function differ with tumor aggressiveness. Identification of these pathways provides a molecular basis for understanding aggressiveness of vSCC.

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Subtype specific analyses reveal Infiltrative Basal Cell Carcinoma are highly interactive with their environment

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