Researchers discover key stem cell dormancy mechanism which could help
unlock future cancer treatments
Study provides insights into how stem cell function could be controlled
and provide new therapeutic targets

Date:
August 3, 2021
Source:
University Health Network
Summary:
Researchers have made new findings which provide a broader
understanding of how dormant hematopoietic stem cells are activated
and could pave the way towards therapeutic treatments for a number
of cancers.



FULL STORY ========================================================================== Princess Margaret Cancer Centre researchers have made new findings which provide a broader understanding of how dormant hematopoietic stem cells
are activated and could pave the way towards therapeutic treatments for
a number of cancers.


==========================================================================
The team has made the discovery by performing a deep mechanistic
study of lysosomes, which are membrane-bound organelles found in all
cells. Lysosomes were once believed to merely be the "garbage bin" of the
stem cell, recycling waste material, regulating cellular regeneration
and functioning the same in all cell types. But the PM team's research
builds on new knowledge about lysosomes which shows they act as key
signaling hubs, regulating long-term hematopoietic stem cells.

Work done by the researchers examines why a hematopoietic stem cell
can remain dormant for years, and how the lysosome constantly acts as a
sensor even in that deeply inactive state. The Princess Margaret team
found that in spite of the cell's dormancy, the lysosome inside it is
still very active, "clipping and inactivating" receptors involved in
growth signaling and nutrient transport within the stem cell membrane,
allowing it to remain asleep.

The findings could have implications beyond the study, potentially
allowing for control of the balance between cell dormancy and when stem
cells are activated to help replenish the blood supply.

The results come from the laboratory of Princess Margaret senior
scientist Dr.

John Dick and are published in Cell Stem Cell on
Aug. 2.,2021. Post-doctoral fellow Dr. Laura Garcia-Prat is first author,
and affiliate scientist Dr.

Stephanie Xie is co-senior author along with Dr. Dick.

"The study has discovered a new mechanism of dormancy, which is to
harness an organelle, a lysosome, and keep that cell dormant," says
Dr. Garcia-Prat. "This opens a way that lysosomes could potentially be harnessed as a therapeutic target." Every year, tens of thousands of
people around the world receive bone marrow transplants to help fight
leukemia. High doses of chemotherapy are used to kill the rapidly dividing cancer cells, but at the same time it also kills stem cells needed to
reproduce healthy blood.



==========================================================================
Stem cell transplants are used to regenerate a patient's heathy blood
supply, but finding a matching donor can be challenging, especially within different ethnic communities where donor lists may not be extensive or
exist at all. Stem cells found in cord blood would have considerable
value as additional donor sources, but the number of stem cells is often
too low for an adult recipient.

Understanding how to activate and expand stem cells in a controlled way
could make cord blood more widely useful.

Being able to control the activation of stem cells might also be useful
for situations where stem cells are inappropriately activated due to
disease, inflammation or drug treatment, helping to restore dormancy to conserve these valuable commodities.

"Learning how to conserve, and preserve, blood stem cells is vital,"
says Dr.

Dick. "If that stem cell gets activated in an inappropriate way that can
have huge consequences for the blood system because you're now losing
your stem cells and you're not going to have that for your lifetime."
"You've got to do everything you can to keep that cell dormant. And one
way you do that is by preventing it from sensing any signals from the
surface," added Dr. Dick.

The work could also be used to help more fully understand leukemia stem
cells which closely mimic regular stem cells and sometimes are able to
go dormant and evade treatments.



==========================================================================
"Now it will be interesting to look at these leukemia stem cells and
see how this mechanism is regulated," says Dr. Stephanie Xie. "We may
see differences and utilize them for treatment." Dr. Garcia-Prat,
the lead author, said this is work could have only done at Dr.

Dick's lab at the Princess Margaret Cancer Centre at the University
Health Network.

"We are one of the few labs in the world working with human hematopoietic
stem cells," says Dr. Garcia-Prat. "So that makes a huge difference in
terms of translating our research into therapies for humans." This work
was supported by the Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research, International Development Research Centre, Canadian Cancer Society, Terry
Fox New Frontiers Program, University of Toronto's Medicine by Design,
the Canada First Research Excellence Fund, EMBO Long-Term Fellowship,
Benjamin Pearl Fellowship and CIHR Fellowship.

========================================================================== Story Source: Materials provided by University_Health_Network. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Laura Garci'a-Prat, Kerstin B. Kaufmann, Florin Schneiter, Veronique
Voisin, Alex Murison, Jocelyn Chen, Michelle Chan-Seng-Yue,
Olga I. Gan, Jessica L. McLeod, Sabrina A. Smith, Michelle
C. Shoong, Darrien Parris, Kristele Pan, Andy G.X. Zeng, Gabriela
Krivdova, Kinam Gupta, Shin-Ichiro Takayanagi, Elvin Wagenblast,
Weijia Wang, Mathieu Lupien, Timm Schroeder, Stephanie Z. Xie,
John E. Dick. TFEB-mediated endolysosomal activity controls
human hematopoietic stem cell fate. Cell Stem Cell, 2021; DOI:
10.1016/j.stem.2021.07.003 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210803105649.htm

--- up 12 weeks, 4 days, 22 hours, 45 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)