Chromatin from dead cancer cells trigger bystander DNA damage and inflammation

Clinical collaborator: Dr. Indraneel Mittra (ACTREC/ TMH)

It is becoming increasingly evident that malignant cells remain in a dynamic inter-relationship with bystander non-malignant cells of the tumour microenvironment at all stages of carcinogenesis. The bystander cells show pro-oncogenic changes characterized by DNA damage and inflammation that contribute to cellular proliferation, survival of malignant cells, angiogenesis and subversion of adaptive immunity. A complex, but poorly understood, network of cytokines, chemokines, growth factors and free radicals drives inter-cellular communication. This work led by Dr. Mittra demonstrates that chromatin fragments from dead cancer cells are the key agents that trigger DNA-damage-repair response (DDR) and inflammation creating a pro-oncogenic milieu in cells of the tumour microenvironment and in those of distant tissues that can promote their cancerous transformation. These findings may have therapeutic implications since neutralizing dead cell-derived chromatin fragments (dcCfs) may prevent the spread of cancer.

To study the effect of dead cancer cells on non-cancerous cells of the tumour microenvironment, Dr. Mittra’s group co-cultured dead cancer cells with NIH3T3 mouse fibroblast cells. They found that numerous chromatin fragments emerged from the dead cancer cells and rapidly entered into nuclei of the recipients triggering DDR which facilitated their incorporation into host cell genomes. Whole genome sequencing (performed in collaboration with Dutt laboratory) detected presence of tens of thousands of human cancer reads in mouse cells when dead human cancer cells were co-cultured with them. Genomic integration was associated with dsDNA breaks, global deregulation of transcription and intense up-regulation of inflammatory cytokines. When injected intravenously into mice, chromatin fragments from dead cancer cells integrated into nuclei of cells of distant tissues activating DDR and inflammation. The above pro-oncogenic pathologies could be abrogated by concurrent treatment with anti-histone antibody complexed nanoparticles (CNPs) both in vitro and in vivo.

Taken together, these findings provide for a new mechanism of cancer metastasis whereby dead cancer cells that lodge in distant organs may induce new cancers by oncogenically transforming host cells via the medium of dcCfs. Such a mechanism of cancer metastasis would be clinically relevant since many tumour cells that circulate in blood of cancer patients (CTCs) are known to be apoptotic. Support for our new proposal comes from the “surprising” observation that patients with breast cancer whose CTCs were enriched in apoptotic cells had a particularly poor prognosis. It has also been reported that, in patients with colorectal cancer, apoptotic CTCs are associated with liver metastasis.

This is the first demonstration that chromatin fragments from dead cancer cells mediate pro-oncogenic changes in the tumour microenvironment and in cells of distant tissues. The fact that CNPs could abrogate these pro-oncogenic pathologies immediately suggests therapeutic possibilities.

(write up by Dr. Indraneel Mittra)

Cell Death Discovery (2017) 3, 17015; doi:10.1038/cddiscovery.2017.15