Metabolic settings of aggressive tumor cells adapt to their energetic and anabolic demands. While limited success in cancer treatment using targeted therapy has been accomplished, the altered metabolism of tumor cells compared to normal cells, provides a viable novel target for a non-toxic chemotherapeutic approach. Since tumor cells can utilize different metabolic strategies that have only now being elucidated, deciphering which metabolic settings are associated to a particular mutational status would be helpful to both design novel therapeutic strategies and stratify patients for treatment. In melanoma ~50% of tumors present activating mutations in BRAF (BRAFV600E) and another 20% present activating mutations in NRAS (NRASQ61L). While targeted therapy of BRAFV600E mutant tumors has been partially successful there is no therapeutic alternative for patients harboring NRASQ61L mutant tumors. Despite the fact that these molecules affect the same pathway (RAS-ERK1/2), BRAFV600E and NRASQ61L mutant cells behave and respond differently to therapy and to metabolic stress. Understanding the metabolic settings of BRAFV600E and NRASQ61L mutant melanoma tumors would help to sensitize them, overcome resistance mechanisms to therapy and target them according to their genetic alterations. This project is been supported by Marie Curie actions.

Expected results: After execution of this project the main expected results are:

1. To define the different metabolic settings of melanomas harboring diferent oncogenic mutations

2. To identify the biochemical mechanism responsible for the differential metabolic stress response acconding to their genotype

3. To design of novel therapeutic alternatives to treat melanoma tumors.

To translate our reseach into the clinic is one of our main objetives. We are currently conducting a preclinical study in colaboration with the Industry to test the therapeutic capabilities of ALDH isoform-specific inhibidors in melanoma, lung and breast tumors. The aims of this project are:

To identify the ALDH isoforms and the metabolic settings associated to oncògenes

To verify a cause and effect relationship between the increased activity of a specific ALDH isoform and the resistance to cell death manifest.

To identify which of the endogenous substrates of ALDH and corresponding reaction products are specifically involved in cell death resistance.

To evaluate the therapeutic efficacy of specific inhibitors of ALDHs

Environmental insults are directly involved in cancer development. In particular, Ultraviolet (UV) radiation has been associated to the acquisition of different types of skin cancer and premature skin aging. UV radiation causes modifications in the genetic material of cells (DNA) that if not repaired properly will lead to a mutated DNA (mutated genes) which might trigger the development of cancer. Understanding the molecular basis of the UV-induced DNA damage response is important to elucidate the mechanisms of skin tumorigenesis.

In the study, published in Plos Genetics, the authors used a UV-induced skin cancer mouse model (Hepatocyte growth factor (HGF) transgenic mice), where one of the two Lkb1 gene alleles was deleted (haploinsufficiency), and consequently the amounts of LKB1 protein was half of the normal levels. A single dose of UVB radiation in Lkb1 haploinsufficient neonates  mice expressing HGF was enough to induced the quickly development of squamous cell carcinomas, and this, was associated to a deficient response in DNA damage repair.  Moreover, cells harboring the damaged DNA were resistant to cell death (apoptosis).  Thus, lack of LKB1 promotes a double effect: cells not only fail to repair the damage in their DNA, but they do not die, leading to the accumulation of mutated cells and the development of tumors. The research team has obtained similar results (to be published soon) in two additional mouse models of melanoma, a much more lethal type of UV-induced skin cancer.

One of the beauties of this model is that reflects the real scenario for cancer adquisition where initially just one of gene copies is damaged. It also reproduces a tumor related to chronic DNA damage using a single dose of UV radiation, underlining the importance of this protein’s function. 

LKB1 mutations have been found epithelial human cancers associated to environmental insults. “However, this is the first study that links LKB1 to the UV-induced DNA repair responses” explains Dr. Recio, “and provides an important insight into how cells can defend themselves from external genotoxic damage”.

Importantly, these results can be extrapolated to human cancer. In fact, when examining the expression of LKB1 protein in samples from patients with skin tumors, the authors found that roughly half of these samples showed low or no expression of LKB1.  Furthermore, absence of the protein was detected in all stages of the disease, particularly in UV-exposed skin areas, suggesting that the loss of expression of LKB1 is an early event and very likely contributes to UV-induced skin cancer development.

In the near future, we will be evaluating LKB1 as a prognostic risk factor for UV–induced skin cancer. They also are investigating the different factors that may alter LKB1 expression, with a particular emphasis in families with skin cancer predisposition or skin cancer history.