Tumour reasons why cancers thrive in chromosomal chaos

Published on: Oct. 26, 2021, 11:02 p.m.

Washington [US], October 26 (ANI): Researchers at the University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumour survival and growth.
The findings appear in the journal European Molecular Biology Organisation.
"In these circumstances, they also co-opt neighbouring cells in a spiral of deceit that progressively impairs local immune cells," said co-senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and a tumour immunologist at Moores Cancer Center with Hannah Carter, PhD, associate professor of medicine and a computational biologist. Zanetti had previously introduced the hypothesis in a Science commentary.
"This was an ambitious goal not attempted before," said Zanetti. "It was like interrogating three chief systems together -- chromosomal abnormalities in toto, signalling mechanisms in response to endogenous stress and dysregulation of neighbouring immune cells -- just to prove a bold hypothesis.
"We knew the task would be challenging," added Carter, "and that we would need to create and refine new analytical tools to test our hypotheses in heterogeneous human tumour data, but it was a worthwhile risk to take."
The findings, they said, show that the stress response in cancer cells serves as an unpredicted link between aneuploidy and immune cells to "diminish immune competence and anti-tumour effects." It also demonstrates that molecules released by aneuploid cells affect another type of immune cells -- macrophages -- by subverting their normal function to turn them into tumour-promoting actors.
The findings offer new opportunities to understand tumour progression as a balance between the progressive accumulation of chromosomal abnormalities during tumour evolution and the progressive decay of anti-tumour immunity, said the authors, with the signalling response to stress gauging and regulating the relationship.
In practical terms, they said, a new aneuploidy score defining the burden of chromosomal abnormalities, developed for the study, could set a new paradigm for assessing the biological stage of tumour progression in patients and be used to extrapolate immune status.
"It may also inform on new opportunities for pharmacological or genetic interventions that interfere with specific branches of the UPR as the mediator of aneuploidy-driven local immune dysregulation. This non-immunological approach could make immunotherapy of cancer more efficient," said Zanetti.
Co-authors include: Su Xian, Magalie Dosset, Gonzalo Almanza, Stephen Searles, Paras Sahani, T Cameron Waller, Kristen Jepsen and Hannah Carter, all at UC San Diego. (ANI)