Oncotarget

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Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma

Maria Inés Molejon, Juan Ignacio Tellechea, Celine Loncle, Odile Gayet, Marine Gilabert, Pauline Duconseil, Maria Belen Lopez-Millan, Vincent Moutardier, Mohamed Gasmi, Stephane Garcia, Olivier Turrini, Mehdi Ouaissi, Flora Poizat, Nelson Dusetti and Juan Iovanna _

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Oncotarget. 2015; 6:7408-7423. https://doi.org/10.18632/oncotarget.3510

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Abstract

Maria Inés Molejon1, Juan Ignacio Tellechea1,2, Celine Loncle1, Odile Gayet1, Marine Gilabert1, Pauline Duconseil1, Maria Belen Lopez-Millan1, Vincent Moutardier1,2, Mohamed Gasmi1,2, Stephane Garcia1,2, Olivier Turrini1,3, Mehdi Ouaissi4, Flora Poizat3, Nelson Dusetti1 and Juan Iovanna1

1 Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

2 Hôpital Nord, Marseille, France

3 Institut Paoli-Calmettes, Marseille, France

4 Hôpital de la Timone, Marseille, France

Correspondence to:

Nelson Dusetti, email:

Juan Iovanna, email:

Keywords: pancreas cancer, xenograft, CD44, recurrence

Received: January 04, 2015 Accepted: February 02, 2015 Published: March 10, 2015

Abstract

It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC.


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