Distinctive desmoplastic 3D morphology associated with BRAFV600E in papillary thyroid cancers.

Distinctive desmoplastic 3D morphology associated with BRAFV600E in papillary thyroid cancers.

J Clin Endocrinol Metab. 2018 Jan 12;:

Authors: Tarabichi M, Antoniou A, Le Pennec S, Gacquer D, de Saint Aubain N, Craciun L, Cielen T, Laios I, Larsimont D, Andry G, Dumont JE, Maenhaut C, Detours V

Abstract
Context: Although 60% of papillary thyroid carcinomas are BRAFV600E mutant (PTCV600E), the higher aggressiveness of these cancers is still debated.
Objective: In PTCV600E we aimed to further characterize the extent of the stroma and its activation, the 3D tumor-stroma interface, and the proliferation rates of tumor and stromal fibroblasts.
Design: We analyzed exomes, trancriptomes and images of 364 PTC from The Cancer Genome Atlas (TCGA), including 211 PTCV600E; stained 22 independent PTC for BRAFV600E and Ki67; sequenced the exomes and stained BRAFV600E in 5 primary tumor blocks and 4 nodal metastases from one PTCV600E patient; and reconstructed the 3D volumes of one tumor and one metastatic blocks at histological resolution.
Results: In TCGA BRAFV600E was associated with higher expression of proliferation markers and lower expression of thyroid differentiation markers, independently of tumor purity. Moreover, PTCV600E, in line with their overall lower purity, also had higher expression of fibroblast- and T-cell-associated genes, and presented more fibrosis. Tumor cells that appeared disconnected on 2D histological slices revealed to be part of a unique tumor component in the 3D reconstructed microvolumes, and formed a surprisingly complex connected space, infiltrating a proliferative stroma. Finally, in our PTC set, both stromal fibroblasts and tumor cells presented higher proliferation rates in PTCV600E.
Conclusions: Our results support the increased aggressiveness associated with BRAFV600E in PTC, and shed light on the important role of the stroma in tumor expansion. The greater and more active fibrotic component predicts better efficiency of combined targeted treatments, as previously proposed for melanomaV600E.

PMID: 29342254 [PubMed - as supplied by publisher]

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