Thursday, March 28

A key genetic mutation in the appearance of lymphomas and lung cancer found in mice

A genetic alteration that affects the VAV1 gene it plays an important role in tumors derived from T lymphocytes (lymphomas) and lung cancer, two types of cancer characterized by very low survival rates. This is the main conclusion of a study led by the Higher Council for Scientific Research (CSIC).

The research group that has carried out this work, which is made up of scientists from the Cancer Research Center (CIC) and the Cancer Network Biomedical Research Center (CIBERONC), have also discovered that this genetic alteration performs different pro-tumor functions depending on the type of organ in which it arises. The work is published in the journal Molecular Oncology.

“Recent genome sequencing studies of a large number of tumors have revealed that they harbor thousands of genetic alterations, the so-called mutations. This has created a new problem: to know which ones are important for the development of cancer or the acquisition of its malignant properties, if they are autonomous or need other genetic alterations simultaneously, and if vulnerabilities associated with these genetic alterations can be identified that allow the development of new antitumor therapies”, explains Xosé R. Bustelowho leads this work and is a researcher at the CIC.

Recent genome sequencing studies of a large number of tumors have revealed that they harbor thousands of genetic alterations, the so-called mutations

Xosé R. Bustelo

Most of these genetic alterations have neutral effects on tumor cells and therefore do not cause the development or malignant progression of tumors that house them. But many of the genetic alterations that do have a relevant role in cancer are found at a very low frequency in patients and, as a consequence, their identification is complex. According to the researchers, this continues to be a great scientific challenge.

“The VAV1 gene was detected in tumors derived from cells that, like T lymphocytes (responsible for our immune responses), did express this gene normally. However, it was also detected in some tumors that, as in lung cancer, were derived from cells that normally did not express this protein. This made us wonder if this genetic alteration was important in both cases and, in this case, try to understand the mechanisms that influence the development of these tumors”, he points out. Javier Robles-Valeroscientist at the CIC (CSIC-USAL) and the Center for Biomedical Research in Network (CIBERONC) and first author of this work.

Other genes involved

The work shows that the spectrum of tumors generated depends on the presence of genetic alterations in two other different genes (TRP53 and KRAS). From a genetically modified mouse model that contained the alteration in the VAV1 gene, the researchers have been able to determine the role of this gene in various types of cancer.

We show that the genetic alteration in VAV1 is not sufficient to induce tumor formation. However, when combined with the deletion of the antitumor gene TRP53, it causes the rapid development of a very specific tumor.

Javier Robles-Valero

“On the one hand, we have shown that the genetic alteration in VAV1 is not enough to induce tumor formation in any organ of the mice. However, when combined with the deletion of the antitumor gene TRP53, it causes the rapid development of a very specific tumor of T lymphocytes known as peripheral T-cell lymphoma. But no other tumor types have been detected, indicating that the combination of these two genetic alterations only gives rise to one type of tumor”, says Robles-Valero.

In the case of lung cancer, the researchers decided to check whether VAV1 mutations require the concurrence of genetic alterations in other genes, since the mice that have genetic alterations that activated the VAV1 genes and at the same time KRAS protumorigenic gene they do develop lung tumors.

“This is probably because, unlike the TP53 gene deletionthe activation of the KRAS gene leads to the expression of VAV1 in lung cells that, under normal conditions, never express this last gene”, indicates Bustelo.

These animal models will serve as the basis to continue studying the progressive development of the two types of tumors and, above all, to test new drugs against them

Javier Robles-Valero

These animal models “They will serve as a basis to continue studying the progressive development of the two types of tumors and, above all, to test new drugs against them, since the results provided by this work have made it possible to identify potential therapeutic targets to eliminate tumors that have the genetic alterations in the VAV1 gene”, concludes Robles-Valero.



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