TLK protein inhibition activates the innate immune system

August 05, 2020

Tousled-like kinases (TLKs) are a potential therapeutic target for cancer treatment due to their central role in DNA repair and replication. The latest work by IRB Barcelona's Genomic Instability and Cancer Laboratory, led by Travis H. Stracker, concludes that TLK inhibition activates the innate immune system, a very important factor in the response to cancer.

"We believe the TLKs are promising targets for cancer therapy and want to understand more about how they work and how cells respond to their reduction or loss," says Stracker. Having headed the Genomic Instability and Cancer Laboratory at IRB Barcelona since 2009, in July this year Stracker took up a new position as group leader at the National Cancer Institute (NIH) in Bethesda, in the US.

Alternative lengthening of telomeres

The group of researchers had previously observed that reduced TLK activity made cancer cells more sensitive to some therapeutic agents. Now, they have found that blocking TLKs triggers an alternative telomere lengthening system (ALT), a pathway used by many cancers, including some of the most aggressive ones like glioblastoma, to maintain telomeres and allow cells to continue dividing.

The group of researchers has discovered that activation of the ALT pathway triggers the innate immune system, potentially attracting immune cells, such as macrophages and T lymphocytes. "The activation of innate immunity in cancer has recently become an active area of research as it has become clear that the innate immune response influences chemotherapy and immunotherapy," comments Stracker.

Genome decondensation and accessibility

In DNA, not all regions have the same function. Some regions contain genes with the information necessary to make proteins, but there are other regions, called heterochromatin, that have a regulatory and structural function, but do not contain genes that give rise to proteins. Another effect of TLK inhibition, observed in this study, is that this heterochromatin, which is usually compacted, ceases to be so, thereby becoming more accessible to the RNA production machinery and leading to an altered composition in the cell.

"This could help us understand our previous observation that TLK depletion caused replication stress and help us exploit the effects of TLK depletion for cancer therapy," says Sandra Segura-Bayona, first author of the study. Segura Bayona is currently a postdoctoral fellow in the laboratory headed by Simon Boulton at The Francis Crick Institute in London.
The project was a collaboration with Camille Stephan-Otto Attolini, head of the IRB Barcelona Bioinformatics Core Facility; Lars Koenig, at the University of Munich, and Simon Boulton, at The Francis Crick Institute. Sandra Segura-Bayona was a PhD student funded by a "La Caixa" International PhD fellowship. Marina Villamor-Paya is funded by an FPI fellowship (by the Spanish Ministry of Science, Innovation and Universities) and the project supported by a grant from the Spanish Ministry of Science, Innovation and Universities.

Institute for Research in Biomedicine (IRB Barcelona)

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to