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Posts Taged cancer-stem-cells

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Targeting of the breast cancer stem cells to improve the treatment of triple negative breast cancer

On April 1st PhD candidate Patricia Cámara Sánchez defended her doctoral thesis entitled “Targeting of the breast cancer stem cells to improve the treatment of triple negative breast cancer“, where ICTS-Nanbiosis Unit 20 participated in the in vivo assays. The thesis was supervised by Dr. Ibane Abasolo  (scientific director of Unit 20 from CIBER-BBN and VHIR). Nanbiosis was also present within the jury, with Dr. Ana Paula Candiota (scientific coordinator of Unit 25 from CIBER-BBN and UAB) acting as secretary.

Patricia Cámara graduated as biochemist, did the master’s degree in Translational Biomedical Research from VHIR-UAB. Shortly after, started the PhD, which was aimed at improving the treatment of very deadly subtype of breast cancer by using different nanoformulations to specifically target the cancer stem cells. The now doctor Cámara-Sánchez screened up to 20 small drugs with anti-cancer stem cell activity, found synergistic ratios with conventional chemotherapeutic agents, and finally developed polymeric micelles encapsulating selected drugs. During the discussion of the dissertation, the need of additional in vivo assays was highlighted, as well as the potential use of MR provided by the U25, to explore non-invasively the metabolomic differences between cancer stem cells and regular cancer cells.

‘I’m very grateful for the opportunity to have been part of this amazing project. It has been a very enriching experience’, she explains. ‘After 5 years of research, I finish the PhD feeling very proud of having contributed to the fight against this aggressive subtype of breast cancer’, she adds. From now on, new research lines will bring forward the synergies between both units of NANBIOSIS, reinforcing a collaboration started several years ago and reflected in joint papers.

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Extracellular vesicles secreted by cancer stem cells promote angiogenesis and disease progression

Patricia González, researcher of the “Drug Delivery and Targeting” of CIBER-BBN and VHIR, presented her thesis work on November 19 where she lays the foundations to understand the role of different subpopulations of extracellular vesicles (VEs) secreted by tumor models in the regulation of tumor plasticity, as well as its effect on the tumor microenvironment and disease progression.

In the project, it has been described for the first time how the VEs secreted by the cancer stem cell subpopulation are responsible for activating fibroblasts in the tumor microenvironment and promoting angiogenesis, thus facilitating disease progression. Furthermore, it has been possible to discern the role of these vesicles in the regulation of cell plasticity. In this sense, the VEs from tumor stem cells would act as effectors of cell differentiation in contrast to the action of the VEs secreted by differentiated cancer cells, which would stimulate the acquisition of stem cell characteristics.

In order to carry out the in vivo experiments, the services of ICTS Nanbiosis were used, through the U20.

The results open a new line of research in the group with a long journey ahead, setting as main objectives the identification of the molecular actors responsible for the activities described above as well as the translation of said knowledge into specific therapeutic strategies.

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Identification of a novel nanotherapy active in cancer cells resistant to chemotherapy

Researchers of the Nanotoxicology Unit (u18-nanotoxicology-unit) led by Ramon Mangues and Isolda Casanova at the Research Institute of the Hospital de Sant Pau and the Protein Production Platform (u1-protein-production-platform-ppp), led by Antonio Villaverde and Neus Ferrer Miralles of the Institute of Biotechnology and Biomedicine at the Autonomous University of Barcelona, both belonging to the ICTS NANBIOSIS (nanbiosis.es) of the CIBER-BBN, have participated in the production of a novel Nanotoxin capable of selectively killing cancer cells which became resistant to chemotherapy. Development of cancer resistance frequently associates with the overexpression of the CXCR4 receptor.

It is known that chemotherapy kills cancer cells, mainly, by induction of apoptosis, after damaging the cell DNA; therefore, to survive resistant cancer cells develop anti-apoptotic mechanisms. In contrast, a Nanotoxin that has incorporated the exotoxin of Corynebacterium diphtheriae and a targeted ligand that selectively internalizes in CXCR4+ cancer cells, exploits a mechanism of cell death alternative to apoptosis, thus, effectively killing resistant cancer cells in a colorectal cancer model.  The new mechanism is the induction of a blockade of protein translation, by inhibition of the elongation factor 2, which renders sensitive to therapy cancer cells resistant to chemotherapy.

The described work opens a new avenue for the exploration of antitumor activity in cancer that relapses after current therapy, an unmet medical need in oncology, and therefore, it could have an important impact in cancer patient well being.

Reference:

Naroa Serna, Patricia Álamo, Prashanthi Ramesh, Daria Vinokurova, Laura Sánchez-García, Ugutz Unzueta, Alberto Gallardo, María Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramón Mangues, Jan Paul Medema. Nanostructured toxins for the selective destruction of drug-resistant human CXCR4 + colorectal cancer stem cells. doi: 10.1016/j.jconrel.2020.01.019.

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AKT2 as a promising target for future anti-cancer therapies

The researchers of NANBIOSIS U20, led by Ibane Abásolo and Simó Schwartz have published a new article on the scientific magazine Cancers, with the title Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

All the in vivo studies were performed by NANBIOSIS U20 In Vivo Experimental Platform.

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potentia

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