Identification of DHTKD1 overexpression as a potential metabolic vulnerability in breast cancer lung metastasis

Details

Supervisors

Sonveaux, Pierre

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enThrough the metastatic process, a primary tumor can colonize distant organs where secondary tumors are formed. These secondary lesions, called metastases, are responsible for 90% of cancer-related patient deaths. In 1889, Stephen Paget formulated the “seed-and-soil” theory, where he proposed that the spread of cancer cells (the “seed”) to specific organs is not random but rather governed by favorable interactions between the cancer cells and the microenvironment of the host organ (the “soil”). More recently, the plasticity of cancer cells, which allows them to proliferate and survive in different environments, has been recognized as a hallmark of cancer. In this study, we hypothesized that specific metabolic traits could constitute vulnerabilities exploitable to treat metastases. Accordingly, we set out to identify the metabolic differences between breast cancer cells and their lung-derived metastases. Using in vitro human triple negative cancer cell models, we genetically, metabolically and phenotypically characterized parental cells MDA-MB-231 and two lung metastatic variant cell lines LMD and LM2 obtained through independent in vivo selections. First, migratory and invasive transwell experiments did not demonstrate a more migratory/invasive phenotype for LMD and LM2. Different metabolic behaviors were identified in lung metastatic variants, comparing to MDA-MB-231 cells. Glycolysis and oxidative phosphorylation were observed to be diminished in lung metastatic derivates. However, ATP levels remained unchanged in the LM2 variant. In parallel, bulk RNA sequencing revealed 28 metabolic genes upregulated in the lung metastatic cell lines compared to parental cells and related bone metastatic variants. After independent RT-qPCR, western blotting and taking into account clinical data, we identified dehydrogenase E1 and transketolase domain containing 1 (DHTKD1), as being upregulated in both the lung metastatic lines. We therefore proceeded by silencing its expression via short hairpin RNA to explore its role in breast cancer cell migration towards human bronchial cells. In conclusion, identifying metabolic vulnerabilities in organ-specific metastases could be a promising approach to treat them, thus avoiding a fatal outcome.