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New Gene Discovery Could Halt Metastatic Cancer Spread – Neuroscience News

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New Gene Discovery Could Halt Metastatic Cancer Spread – Neuroscience News

Summary: A new study identifies the Gstt1 gene as crucial for metastatic cancer cell growth. Researchers found that silencing Gstt1 in metastatic cells prevents their spread.

This gene helps cancer cells modify their environment, facilitating growth in new body locations. The findings offer potential new therapeutic strategies to target metastatic cancer, especially in aggressive types like pancreatic cancer.

Key Facts:

  1. Gstt1 gene expression is essential for metastatic cancer cell growth.
  2. Silencing Gstt1 hinders the spread of metastatic cells in both mouse and human models.
  3. Gstt1 modifies the extracellular matrix, aiding cancer cell attachment and growth.

Source: Mass General

Metastatic cancer cells, which cause 90% of cancer-related deaths, must overcome numerous hurdles to spread from a primary tumor through the bloodstream.

A new study led by investigators from the Mass General Cancer Center has identified a gene whose expression confers a growth advantage to these cells.

Mechanistically, the gene’s expression allows metastatic cancer cells to cause changes to their surrounding environment so that they can grow in new locations in the body. The findings are published in Nature Cell Biology.

In these experiments, silencing the Gstt1 gene had no effect on primary tumor cells from mice, but it stripped metastatic cancer cells of their ability to grow and spread. Credit: Neuroscience News

“Our results point to potentially novel therapeutic avenues to specifically target metastatic cancer,” said senior author Raul Mostoslavsky, MD, PhD, who is the scientific director of the Krantz Family Center for Cancer Research at the Mass General Cancer Center.

Mostoslavsky and colleagues first compared gene expression patterns in primary versus metastatic tumors in mice with pancreatic cancer or breast cancer. After identifying various genes whose expression increased in metastatic tumor cells, the researchers silenced each gene individually.

In these experiments, silencing the Gstt1 gene had no effect on primary tumor cells from mice, but it stripped metastatic cancer cells of their ability to grow and spread. It also blocked cell growth in two metastatic-derived human pancreatic cancer cell lines.

Gstt1 encodes an enzyme that is a member of a superfamily of proteins involved with protecting cells from toxins, among other functions. Mechanistic studies indicated that the Gstt1 enzyme causes metastatic cancer cells to modify and secrete a protein called fibronectin, which is important for helping cells to attach themselves to the extracellular matrix, a large network of proteins and other molecules that surround, support, and give structure to cells and tissues in the body.

“Gstt1 alters the matrix surrounding the metastatic cells so they can grow in these foreign niches,” said Mostoslavsky.

“Our results could lead to new strategies for the treatment of metastatic disease. This would be especially impactful for pancreatic cancer, in which most patients present with metastases when initially diagnosed.”

Funding: This research was supported by the National Institutes of Health, the American Cancer Society, the Maryland Department of Health, and the National Cancer Institute.

About this genetics and cancer research news

Author: Liz Murphy
Source: Mass General
Contact: Liz Murphy – Mass General
Image: The image is credited to Neuroscience News

Original Research: Closed access.
The glutathione S-transferase Gstt1 drives survival and dissemination in metastases” by Ferrer CM et al. Nature Cell Biology


Abstract

The glutathione S-transferase Gstt1 drives survival and dissemination in metastases

Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA).

A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. 

Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours.

This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial–mesenchymal transition features and DTC characteristics compared to the Gstt1low population.

Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment.

We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.

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