Characterization of bioactive molecules derived from marine microorganisms, interfering with cell dedifferentiations observed at the invasive front of mammary tumors

Breast cancer is the leading cause of cancer death in women. At the in situ carcinoma stage the tumor can be surgically removed, but in later stages tumor cells can undergo epithelial-to-mesenchymal transition (EMT) [1], become invasive and chemoresistant [2]. To date, research on therapy targeting EMT [3] does not consider cellular heterogeneity of the tumor. Indeed, tumor cells communicate particularly with adipocytes [4], resulting in an EMT, a loss of estrogen receptors and adipocyte dedifferentiation. Recent examples of marine products interfering with these dedifferentiation processes have been highlighted [5]. In addition, marine biodiversity, from which microorganisms [6], already led to several drugs on the market [7], especially in oncotherapy.

Our experimental strategy is to isolate and characterize molecules extracted from 70 fungal strains associated to brown algae and cultivated in two conditions. Extracts and molecules are selected on their ability to inhibit tumor cell invasion, and adipocyte-tumor cell communication by measuring both cell line differentiation states. A first viability assay has shown that 16 strains have high cytotoxic effects (IC50 < 25 µg/mL). A strain from the marine fungus Paradendryphiella arenaria was particularly efficient with an IC50 of 1 µg/mL on MCF7 epithelial cancer cell lines and 0.7 µg/mL on MCF7-Sh-WISP2 invasive cancer cell lines. The chemistry of this fungus is poorly studied. An ongoing purification and dereplication step, will allow for isolation of potentially new bioactive molecules.

These experiments let us bring out, yet, non studied marine fungal crude extracts that have an anticancer activity, not only on non-invasive mammary cancer cells, but also on invasive ones, which constitute their strong therapeutic potential.

Acknowledgements: The UPMC through the PDIF and Lapervenchelif are acknowledged for their financial support.

Keywords: Breast cancer, EMT, marine natural products, fungal endophytes, Paradendryphiella arenaria.

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