Research
Protease, Microenvironment and Cancer : E. Liaudet-Coopman

Research topics

 
 

Breast cancer (BC) is one of the leading causes of death in women in developed countries.  Triple-negative BC (TNBC) defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) overexpression and/or amplification, accounts for 15-20% of all BC cases. Resistance to systemic treatment is common, particularly in TNBC. Hence, tumor-specific molecular targets and/or alternative therapeutic strategies for BC are urgently needed. With the discovery of antigens specifically expressed in BC cells and the developing technology of monoclonal antibodies, immunotherapy targeting the tumor microenvironment is emerging as a novel promising option.

 

A solid tumor is an ecosystem composed of tumor cells, resident and infiltrating non-tumor cells, and molecules present in proximity to these cells. This ecosystem can be collectively described as the tumor microenvironment. Both the tumor cells as well as the neighboring non-tumor cells take part in establishing the specific milieu of the microenvironment. The notion that the tumor microenvironment plays a crucial role in cancer development and in its progression is generally accepted by the cancer research community. In solid tumors, cancer and stromal cells secrete abnormal levels/types of growth factors, cytokines, matrix proteins, and proteases, leading to a tumor-specific microenvironment.

 

Our team actively participated in the contemporary highly dynamic field that aims to unravel the non-classical roles of proteases in BC: the signaling role of extracellular cathepsin D (cath-D) and the significance of the newly described nuclear form of the protease.

Cath-D is a well-established independent marker of poor prognosis for BC. Cath-D is overproduced by BC cells and the pro-enzyme is hyper-secreted into the tumor microenvironment (see figure below).

 

 

 

Our team has made major contributions to the understanding of unconventional roles of cathepsin D in BC and in the tumor microenvironment. Cath-D stimulates BC cell proliferation, fibroblast outgrowth, angiogenesis, breast tumor growth and metastasis formation. Cath-D can affect BC progression via mechanisms implicating or not its proteolytic activity. At the tumor acidic pH, secreted cath-D degrades cystatin C, the most potent extracellular inhibitor of cysteine cathepsins, thus promoting their proteolytic activity within the tumor microenvironment. Alternately, secreted cath-D interacts with the fibroblastic LDL receptor-related protein-1 (LRP1) and inhibits LRP1-regulated intramembrane proteolysis (RIP), leading to fibroblast outgrowth. Therefore, extracellular cath-D could represent a novel target in BC.

 

Meanwhile, we also discovered that cath-D was localized in ER+ BC cell nuclei, and showed that the cath-D nuclear targeting was controlled by BAT3 (see figure below), a nucleocytoplasmic shuttling BAT3 essential for starvation-induced autophagy by modulating p300-dependent acetylation of ATG7 and p53. Nuclear cath-D acted as a transcriptional cofactor of TRPS1 (tricho-rhino-phalangeal-syndrome 1), a repressor of GATA-mediated transcription, to regulate ER+ BC cell proliferation and transformation in a non-proteolytic manner (see figure below).

 

 

These last years, we have initiated the targeting of the cath-D aberrantly secreted in massive excess into the breast tumor microenvironment with the support from LabEx MabImprove*. This translational project was designed to inhibit the pathophysiological cath-D activity in the breast tumor microenvironment of TNBC using therapeutic high affinity specific anti-cath-D human monoclonal antibodies. We demonstrated that cath-D-specific antibody triggered tumor growth inhibition by favoring natural killer cell activation, anti-tumor cytokine production, and preventing the recruitment of M2-polarized macrophages and myeloid derived suppressor cells within the tumor, a specific effect associated with a less immunosuppressive tumor microenvironment in TNBC.

 

*Our team is strongly implicated in the LabEx MAbImprove since 2011 (http://mabimprove.univ-tours.fr).

 


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