Tapping into an ancient evolutionary survival mechanism, cancer cells enter
into a sluggish, slow-dividing state to survive the harsh environment
created by chemotherapy or other targeted agents.
In research published January 7 in Cell, Princess Margaret Cancer Centre
scientist Dr. Catherine O'Brien and team discovered that when under threat,
all cancer cells – rather than just a subset – have the ability to
transition into this protective state, where the cells "rest" until the
threat, or chemotherapy, is removed.
It is the first study to identify that cancer cells hijack an evolutionary
conserved program to survive chemotherapy. Furthermore, the researchers show
that novel therapeutic strategies aimed at specifically targeting cancer
cells in this slow-dividing state can prevent cancer regrowth.
"The tumour is acting like a whole organism, able to go into a slow-dividing
state, conserving energy to help it survive," says Dr. O'Brien, who is also
an Associate Professor in the Department of Surgery at the University of
Toronto (U of T).
"There are examples of animals entering into a reversible and slow-dividing
state to withstand harsh environments.
"It appears that cancer cells have craftily co-opted this same state for
their survival benefit."
Dr. Aaron Schimmer, Director of the Research Institute and Senior Scientist
at the Princess Margaret, notes that this research shows that cancer cells
hibernate, like "bears in winter."
He adds: "We never actually knew that cancer cells were like hibernating
bears. This study also tells us how to target these sleeping bears so they
don't hibernate and wake up to come back later, unexpectedly.
"I think this will turn out to be an important cause of drug resistance, and
will explain something we did not have a good understanding of previously."
Using human colorectal cancer cells, the researchers treated them with
chemotherapy in a petri dish in the laboratory.
This induced a slow-dividing state across all the cancer cells in which they
stopped expanding,requiring little nutrition to survive. As long as the
chemotherapy remained in the dish, the cancer cells remained in this state.
In order to enter this low-energy state, the cancer cells have co-opted an
embryonic survival program used by more than 100 species of mammals to keep
their embryos safe inside their bodies in times of extreme environmental
conditions, such as high or low temperatures or lack of food.
In this state, there is minimal cell division, greatly reduced metabolism,
and embryo development is put on hold. When the environment improves, the
embryo is able to continue normal development, with no adverse effects on
the pregnancy.
Dr. O'Brien, who is a surgeon specializing in gastrointestinal cancer,
explains that cancer cells under attack by the harsh chemotherapy
environment are able to adopt the embryonic survival strategy.
"The cancer cells are able to hijack this evolutionarily conserved survival
strategy, even as it seems to be lost to humans," she says, adding that all
of the cancer cells enter this state in a co-ordinated manner, in order to
survive.
Remembering a talk three years ago on cellular mechanisms driving this
survival strategy in mouse embryos, Dr. O'Brien had an "Aha!" insight.
"Something clicked for me when I heard that talk," she said. "Could the
cancer cells be hijacking this survival mechanism to survive chemotherapy?"
So Dr. O'Brien contacted the Toronto Mount Sinai Hospital researcher Dr.
Ramalho-Santos who had given the original talk at the Princess Margaret.
She compared the gene expression profile of the cancer cells in the
chemotherapy-induced, slow-dividing state to the paused mouse embryosin Dr.
Ramalho-Santos' lab, and found that they were strikingly similar.
Similar to embryos, cancer cells in theslow-dividing state require
activation of the cellular process called autophagy, meaning
"self-devouring." This is a process in which the cell "devours" or destroys
its own proteins or other cellular components to survive in the absence of
other nutrients.
Dr. O'Brien tested a small molecule that inhibits autophagy, and found that
the cancer cells did not survive. The chemotherapy killed the cancer cells
without this protective mechanism.
"This gives us a unique therapeutic opportunity," says Dr. O'Brien. "We need
to target cancer cells while they are in this slow-cycling, vulnerable state
before they acquire the genetic mutations that drive drug-resistance.
"It is a new way to think about resistance to chemotherapy and how to
overcome it."
Reference:
Sumaiyah K. Rehman et al. Colorectal Cancer Cells Enter a Diapause-like DTP
State to Survive Chemotherapy. Cell, 2021 DOI:
10.1016/j.cell.2020.11.018