Irene Lasheras Otero, a predoctoral researcher at the Cancer Signaling Research Unit of Navarrabiomed-IdiSNA, will present her doctoral thesis at the Public University of Navarra on Wednesday, June 28th, at 11:00 a.m. in the Navarrabiomed auditorium. The thesis, entitled “Metabolic Regulation of Anoikis and Implications in Melanoma Metastasis” has been conducted at Navarrabiomed under the supervision of Dr. Imanol Arozarena Martinicorena, Principal Investigator of the Cancer Signaling Research Unit at Navarrabiomed. Irene’s research aims to identify relevant mechanisms in the survival of circulating melanoma tumor cells.

Research Development and Results

Melanoma is a type of skin cancer with a special capacity to produce metastases, which cause 90% of cancer-related deaths. Metastases originate from tumor cells that leave the primary tumor, enter the bloodstream, and spread throughout the body.
Circulating tumor cells are the key link between a primary tumor and distant metastases. Generally, in the bloodstream, the loss of adhesion of circulating tumor cells leads to cell death (anoikis), therefore these cells must develop resistance to anoikis in order to later colonize organs such as the lungs, liver, or brain.

During her doctoral thesis, Irene has focused on analyzing these resistance mechanisms via RNA sequencing analysis. The results obtained demonstrate that both suspended melanoma cells and circulating melanoma tumor cells reconfigure lipid metabolism by inducing fatty acid (FA) transport and genes related to FA beta-oxidation. In melanoma patients, the high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with lower overall survival and progression-free survival.

Furthermore, the findings reveal that carnitine transferases, specifically octanoyl transferase and acetyl transferase, are some of the most highly expressed regulators in circulating melanoma tumor cells. These proteins control the transport of medium-chain FAs produced in the peroxisome to the mitochondria to fuel mitochondrial beta-oxidation. Inhibition of octanoyl transferase or acetyl transferase, and short-term treatment with thioridazine or ranolazine (inhibitors of peroxisomal and mitochondrial FA beta-oxidation, respectively), suppressed melanoma metastasis formation in mice.

Moreover, to gain a more comprehensive understanding of the metabolic mechanisms that regulate anoikis resistance, a study was conducted using CRISPR-Cas9, which identified the mitochondrial electron-transport chain and cholesterol metabolism as potential mediators of anoikis resistance in melanoma.

Funding and Dissemination of Results
This research has been funded by the Carlos III Health Institute and the Navarrabiomed 2019 predoctoral grant program. Additionally, in 2022, Irene conducted a six-month stay in Dr. James Olzmann’s laboratory at the University of California, Berkeley, thanks to a travel fellowship from the European Association for Cancer Research (EACR).

The work conducted has resulted in a scientific publication, in February 2023, in the Journal of Investigative Dermatology, entitled “The Regulators of Peroxisomal Acyl-Carnitine Shuttle CROT and CRAT Promote Metastasis in Melanoma.”

Furthermore, the results have been disseminated at various scientific conferences, including the UCSF-UCB Liver Metabolism Symposium in Berkeley, California, in 2020, and the Seed and Soil: Mechanism of Metastasis conference organized by the EACR in Berlin.