Lymphoma: Key signaling pathway involved in tumor formation identified


Date:
January 12, 2022
Source:
Charite' - Universita"tsmedizin Berlin
Summary:
There are myriad reasons why cancers develop. By studying genes
which are altered in people with lymphoma, a multidisciplinary
team of researchers has identified a key mechanism involved in
disease development. This signaling pathway, which the researchers
describe in detail, controls the repair of DNA damage.



FULL STORY ========================================================================== There are myriad reasons why cancers develop. By studying genes
which are altered in people with lymphoma, a multidisciplinary team
of researchers, led by Charite' -- Universita"tsmedizin Berlin and
Goethe University Frankfurt, have identified a key mechanism involved
in disease development. This signaling pathway, which the researchers
describe in detail, controls the repair of DNA damage. Published in
Nature Communications, these findings could open potential new avenues
for treatment.


========================================================================== Cancer is associated with the disruption of various cellular signaling pathways. One of these pathways, 'SUMOylation', is responsible for
the targeted modification of proteins, determining factors such as
their lifespan and location within the cell. "As part of our study,
we identified a previously unknown cancer gene, which controls this key
cancer signaling pathway and could therefore offer a target for new cancer treatments," says Prof. Dr. Ulrich Keller, Head of the Department of Hematology, Oncology and Cancer Immunology on Charite''s Campus Benjamin Franklin and Group Leader (Keller Lab) at the Max Delbru"ck Center for Molecular Medicine (MDC).

In an effort to identify and characterize these central control
mechanisms, a team of researchers, led by Charite' and Goethe University, systematically searched for genes which are found to be altered in
lymphoma (cancer of the lymphatic system). Working with a mouse model,
the researchers opted for a 'transposon system', a tool which utilizes
mobile DNA segments (known as transposons or 'jumping genes') to randomly switch individual genes on and off in order to study their effects on
tumor development. "Numerous large sequencing studies conducted over
the past few years have produced detailed characterizations of cancer
genomes, visualizing the complexity and heterogeneity of underlying modifications using 'molecular maps'. However, these abnormalities often
only occur in small groups of patients, rendering any interpretation of
their significance more difficult," explains first author Dr.

Markus Schick, Team Leader and Principal Investigator at Charite''s
Department of Hematology, Oncology and Cancer Immunology. He adds:
"Our approach enabled us to identify many previously unknown cancer
genes -- among them the SENP6 gene, which is missing in approximately
one third of all lymphoma patients. On the basis of this discovery,
we then established the gene's mechanism of operation and developed
a treatment strategy." The gene's role in cancer pathology had not
previously been understood. SENP6, the protein encoded by this gene,
removes SUMO modifications from other proteins inside the cell. By doing
so, it also controls the proteins' interactions with one another. The
research team were able to prove that switching off SENP6 leads to cancer development, meaning it acts as a tumor suppressor. In healthy cells,
SENP6 plays a key role in the repair of DNA damage. Loss of the gene
results in this function being impaired. This leads to an accumulation
of DNA damage which ultimately facilitates cancer development.

In this study, however, the researchers were able to effectively suppress cancer growths following the loss of SENP6. They did so by inhibiting
PARP, an enzyme involved in the repair of DNA damage, using drugs already licensed for breast cancer treatment. "Combining the biochemical expertise available at Frankfurt with the lymphoma and mouse genetics expertise at Charite' in Berlin was key to the success of this project," emphasizes
Prof. Dr. Stefan Mu"ller, whose research group at Goethe University's
Institute of Biochemistry II was involved in characterizing the SENP6
protein's function.

Summarizing the research, Prof. Keller says: "Our findings enabled us
to establish SENP6 as a biomarker for treatment success following PARP inhibitor therapy. We are currently investigating whether the mechanism described here might also be contributing to the development of cancers
other than lymphoma." He continues: "The aim of personalized medicine
is to develop treatments which precisely match the specific needs of the individual patient. The next step, therefore, will be to conduct clinical studies to test whether these inhibitors offer an innovative, targeted treatment option in cancers characterized by the loss of SENP6. There is
also the option of using them as part of combination therapy regimens,
which are still too rarely used but hold enormous potential, particularly
when they are selected based on an individual patient's tumor biology."
special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> academy.newscientist.com/courses/science-of-sleep-and-dreams ========================================================================== Story Source: Materials provided by
Charite'_-_Universita"tsmedizin_Berlin. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Markus Schick, Le Zhang, Sabine Maurer, Hans Carlo Maurer,
Konstandina
Isaakaidis, Lara Schneider, Upayan Patra, Kathrin Schunck, Elena
Rohleder, Julia Hofstetter, Apoorva Baluapuri, Anna Katharina
Scherger, Julia Slotta-Huspenina, Franziska Hettler, Julia Weber,
Thomas Engleitner, Roman Maresch, Jolanta Slawska, Richard Lewis,
Rouzanna Istvanffy, Stefan Habringer, Katja Steiger, Armin Baiker,
Robert A. J.

Oostendorp, Cornelius Miething, Hans-Peter Lenhof, Florian
Bassermann, Bjo"rn Chapuy, Matthias Wirth, Elmar Wolf, Roland Rad,
Stefan Mu"ller, Ulrich Keller. Genetic alterations of the SUMO
isopeptidase SENP6 drive lymphomagenesis and genetic instability
in diffuse large B-cell lymphoma.

Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-021-27704-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220112105640.htm
--- up 5 weeks, 4 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)