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

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

doi:10.18632/oncotarget.3510

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, due to early metastases and strong chemoresistance [1, 2]
Since the expression of cancer stem cells (CSCs) markers does not predict the responsiveness to the anticancer treatments, we further studied whether CSC-like cells, present in the residual tumors, are insensitive to the most commonly used PDAC chemotherapeutics
By using direct xenografting from human PDACs, that, following robust treatment with gemcitabine, relapsing tumors are formed mainly from CD44+ cells. This indicates that CD44 is the most promising target for treating PDAC tumors after firstline therapy

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, due to early metastases and strong chemoresistance [1, 2]. This chemoresistance is due, in part, to the characteristic stromal composition of these cells, which acts as a mechanical barrier, and the subsequent reduced vascularization of the cellular environment, both of which interfere with the ability of drugs to reach the target cells [3]. The variation in expression of these cancer cell properties generates diverse grades of PDAC resistance, each of which requires adapted treatment, which may in turn affect survival time for patients. The possibility that residual tumors may result from a combination of both a selection of resistant cells along with an expansion of a marginal population of naturally insensitive cells, cannot be excluded

Methods

Results

Conclusion