Retrotransposons facilitates tissue specific horizontal transfer of circulating tumor DNA between human cells

Abstract

A variety of organisms have been shown to have altered physiology or developed pathology as a result of gene transfer, but mammals has never been shown to do so. Here, we show that circulating tumor DNA (ct) can promote cell-specific horizontal gene transfer (HGT) between human cancer cells and explain the mechanisms behind this phenomenon. Once ctDNA enters the host cell, it migrates to the nucleus and integrate into the cells genome, thereby transferring its genetic information. We determine that retrotransposons of the ERVL, SINE, and LINE families are necessary for cell targeting and the integration of ctDNA into host DNA. By using chemically synthesized retrotransposons, we found that AluSp and MER11C reproduced multiple myeloma (MM) ctDNAs cell targeting and integration into MM cells. We also discovered that ctDNA may, as a result of HGT, influence the treatment response of multiple myeloma and pancreatic cancer models. Overall, this is the first study to show that retrotransposon-directed HGT can promote genetic material transfer in cancer. There is, however, a wider impact of our findings than just cancer, since cell free DNA has also been found in physiological and other pathological conditions as well. Furthermore, with the discovery of transposons-mediated tissue specific targeting, a new avenue for the delivery of genes and therapies will emerge.

A retrotransposon-derived DNA zip code internalizes myeloma cells through Clathrin-Rab5a-mediated endocytosis

“…Direct comparison of MM-ZC with other DNA sequences demonstrated the specific and significant internalization of MM-ZC in MM1R, other widely used myeloma cell lines. This result is similar to that of MM1S cells whose data is present in elsewhere (1) and demonstrated a significant uptake of MM-ZC compared to the other DNA sequences (Figure 2A, compare MM-ZC bar graph with other DNA sequences). Both trypsin-treated and untreated cells showed similar patterns.…”

“…Previously we have demonstrated a significant discovery related to horizontal gene transfer (HGT) in the context of cancer, explicitly involving cell-free DNA circulating tumor DNA (ctDNA) as a vehicle for transferring genes between cancer cells. Our pioneering study revealed that retrotransposons, specific mobile elements within the ctDNA, play a central role in mediating HGT in cancer (1). Retrotransposons are sequences capable of moving within the genome, and their reactivation in cancer cells may facilitate their integration into the cancer cell genome.…”

“…Retrotransposons are sequences capable of moving within the genome, and their reactivation in cancer cells may facilitate their integration into the cancer cell genome. We showed that ctDNAderived sequences could serve as a vehicle for transferring genetic material between cancer cells by using various reporters as a delivery cargo to target cancer cells (1). However, the specific cellular mechanism by which ctDNA is recognized and internalized by target cancer cells is unknown.…”

“…Horizontal gene transfer (HGT) is the mechanism by which genes transfer between cells and impact genome evolution and regulation (1). Transposons play a significant role in HGT in eukaryotes, such as insects and plants (2).…”

Unveiling retrotransposon-derived DNA zip code for myeloma cell internalization

“…We showed that ctDNA naturally has an affinity for recipient cells that are phenotypically and genotypically similar to the donor cells. By identifying the DNA sequences at ctDNA insertion sites and demonstrating that synthetically generated transposon sequences can deliver payloads to target cells, therefore, we proved that these zip code sequences play a pivotal role in HGT communication by mediating targeted interactions between donor and recipient cells, facilitating the transfer of genetic material or signaling molecules [ 31 ].…”