Oncotarget

Research Papers:

EGFR is involved in dermatofibrosarcoma protuberans progression to high grade sarcoma

Amélie Osio _, Shuo Xu, Morad El Bouchtaoui, Christophe Leboeuf, Guillaume Gapihan, Christine Lemaignan, Guilhem Bousquet, Céleste Lebbé, Anne Janin, Maxime Battistella

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Oncotarget. 2018; 9:8478-8488. https://doi.org/10.18632/oncotarget.23899

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Abstract

Amélie Osio1,2, Shuo Xu2, Morad El Bouchtaoui1,2, Christophe Leboeuf2, Guillaume Gapihan2, Christine Lemaignan3, Guilhem Bousquet2,4,5, Céleste Lebbé6,7, Anne Janin1,2 and Maxime Battistella1,2

1Pathology Department, Hôpital St Louis, APHP, Paris, France

2Université Paris Diderot, Inserm, UMR_S1165, Paris, France

3Oncology Department, Hôpital St Louis, APHP, Paris, France

4Oncology Department, Hôpital Avicenne, Bobigny, France

5Université Paris 13, Villetaneuse, France

6Dermatology Department, Hôpital St Louis, Paris, France

7Université Paris Diderot, Inserm, UMR_S976, Paris, France

Correspondence to:

Maxime Battistella, email: maxime.battistella@aphp.fr

Keywords: soft tissue sarcoma; dermatofibrosarcoma protuberans; tumor heterogeneity; EGFR; SNAIL

Received: June 10, 2017     Accepted: November 10, 2017     Published: January 03, 2018

ABSTRACT

Dermatofibrosarcoma protuberans (DFSP), amounting to 6% of all soft tissue sarcomas, has a slow growth rate, contrasting with a likelihood for local recurrence and a 10-20% evolution to higher-grade sarcoma, or “transformed DFSP” (DFSP-T). At molecular level, the characteristic COL1A1-PDGFB rearrangement, leading to sustained PDGFR signaling, is not linked to the evolutive potential. Here, we studied EGFR, another tyrosine kinase receptor, using laser-microdissection to select the different histologic components of DFSP (DFSP center, DFSP infiltrative periphery, DFSP-T higher-grade sarcoma), in 22 patients followed over 3 to 156 months. EGFR protein and mRNA were expressed in 13/22 patients with DFSP or DFSP-T, and increased with tumor progression, both in microdissected areas of higher-grade sarcomas and in microdissected areas of local extension. No cancer-associated EGFR gene mutation or copy-number variation, nor any KRAS, BRAF, NRAS hotspot mutations were found in any microdissected area. Among epithelial-mesenchymal transition factors tested, SNAIL 1/2 had the same expression pattern as EGFR while ZEB1/2 or TWIST1/2 did not. Using a proteome profiler phospho-kinase array on 3 DFSP and 3 DFSP-T cryopreserved tissue samples, EGFR phosphorylation was detected in each case. Among EGFR downstream pathways, we found positive correlations between phosphorylation levels of EGFR and STAT5a/b (r = 0.87, p < 0.05) and TOR (r = 0.95, p < 0.01), but not ERK in the MAPK pathway (r = -0.18, p > 0.70). We thus demonstrated that in DFSP evolution to high grade sarcoma, EGFR and SNAIL were involved, with EGFR activation and signaling through TOR and STAT5a/b downstream effectors, which could lead on to new therapies for advanced DFSP.


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