Researchers led by Didier Trono’s group at EPFL have uncovered a crucial survival tactic employed by cancer cells. The scientists identified a group of proteins, known as KRAB zinc finger proteins (KZFPs), that help cancer cells maintain genetic stability and avoid immune system detection.

Their findings are published in Cancer Research in an article titled, “A cluster of evolutionarily recent KRAB zinc finger proteins protects cancer cells from replicative stress-induced immunogenic inflammation.”

“Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses that promote immune rejection,” the researchers wrote. “KRAB domain-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TE). Here, we identified an association of upregulation of a cluster of primate-specific KZFPs with poor prognosis, increased copy-number alterations, and changes in the tumor microenvironment in diffuse large B-cell lymphoma (DLBCL).”

The new study, led by Filipe Martins, a scientist in Trono’s group, reveals a correlation between a subset of primate-specific KZFPs and the prognosis of diffuse large B cell lymphoma. The researchers used advanced cell culture techniques, genetic manipulation via short hairpin RNAs (shRNAs), and genomic profiling methods to observe the effects of depleting two specific KZFPs in tumor cells from various types of cancers, including diffuse large B cell lymphoma.

Depleting ZNF587 and ZNF417 in diffuse large B cell lymphoma cells led to significant disruptions in cellular processes. The loss of these proteins resulted in the redistribution of heterochromatin, which created replicative stress, a condition where DNA replication is impeded, which can slow or stall cell division.

“Our study shows that TE regulation and heterochromatin maintenance by KZFPs is essential also in cancer, which allowed us to uncover new functions of KZFPs, previously overlooked in cancer research due to their young evolutionary age and presumed redundancy,” explained Trono, who is a professor at EPFL.

He added: “Three-quarters of KZFP genes are primate-restricted, challenging the conventional wisdom that the more conserved a protein is, the more essential it should be for cancer development. Our findings indicate that KZFPs not only regulate gene expression but also participate in DNA replication and genome stability, which can influence the genetic diversity and occurrence of subclonal populations of cancer cells, thus playing a pro-oncogenic role.”

“This DNA damage and ‘viral mimicry’ of TEs due to their upregulation led to the activation of cell-intrinsic inflammatory pathways promoting immune rejection in vitro,” added Filipe Martins. “These phenomena have so far been seen only with chemotherapy agents or depletion of cellular enzymes. Therefore, targeting transcription factors holds the promise of a potential immunogenic chemotherapy-like effect.”

The findings suggest that cancer cells may exploit these proteins to mask their visibility to immune surveillance. “It is a true conceptual breakthrough,” said Trono. “Transposable elements, which most consider only as genetic threats, were revealed to be sentinels against loss of epigenetic controls, and their KZFPs regulators were shown to be subverted by cancer cells to escape this surveillance.”

The findings also pave the way for potential new targets for therapy of diffuse large B cell lymphoma. “The discovery points immediately to novel therapeutic avenues for this disease,” said Trono. “It is a line of research for which we are currently raising funds for a large consortium comprising several groups from EPFL in addition to others from Stanford, the Curie Institute, Cornell, the van Andel Institute, and London’s Bart Institute, and we are also working towards the launching of a startup.”

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