Abstract A variety of organisms have been shown to have altered physiology or developed pathology due to gene transfer, but mammals have 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 integrates into the cell’s 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. Using chemically synthesized retrotransposons, we found that AluSp and MER11C reproduced multiple myeloma’s (MM) ctDNA’s cell targeting and integration into MM cells. We also discovered that ctDNA might, 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 broader 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.

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