Reawakening the Developmental Origins of Cancer Through Transposable Elements

Abstract

Transposable elements (TEs) have an established role as important regulators of early human development, functioning as tissue-specific genes and regulatory elements. Functional TEs are highly active during early development, and interact with important developmental genes, some of which also function as oncogenes. Dedifferentiation is a hallmark of cancer, and is characterized by genetic and epigenetic changes that enable proliferation, self-renewal and a metabolism reminiscent of embryonic stem cells. There is also compelling evidence suggesting that the path to dedifferentiation in cancer can contribute to invasion and metastasis. TEs are frequently expressed in cancer, and recent work has identified a newly proposed mechanism involving extensive recruitment of TE-derived promoters to drive expression of oncogenes and subsequently promote oncogenesis-a process termed onco-exaptation. However, the mechanism by which this phenomenon occurs, and the extent to which it contributes to oncogenesis remains unknown. Initial hypotheses have proposed that onco-exaptation events are cancerspecific and arise randomly due to the dysregulated and hypomethylated state of cancer cells and abundance of TEs across the genome. However, we suspect that exaptationlike events may not just arise due to chance activation of novel regulatory relationships as proposed previously, but as a result of the reestablishment of early developmental regulatory relationships. Dedifferentiation in cancer is well-documented, along with expression of TEs. The known interactions between TEs and pluripotency factors such as NANOG and OCTt4 during early development, along with the expression of some placental-specific TE-derived transcripts in cancer support a possible link between TEs and dedifferentiation of tumor cells. Thus, we hypothesize that onco-exaptation events can be associated with the epigenetic reawakening of early developmental TEs to regulate expression of oncogenes and promote oncogenesis. We also suspect that activation of these early developmental regulatory TEs may promote dedifferentiation, although at this stage it is hard to predict whether TE activation is one of the initial drivers of dedifferentiation. We expect that developmental TE activation occurs as a result of the establishment of an epigenetic landscape in cancer that resembles that of early development and that developmental TE activation may also enable cancers to exploit early developmental pathways, repurposing them to promote malignancy.

Specific N-cadherin–dependent pathways drive human breast cancer dormancy in bone marrow

“…Once in the BM, BCCs evoke the resident BM niche cells (such as macrophages, fibroblasts, and mesenchymal stem cells [MSCs]) to facilitate their transition into a dormant phase ( Rao et al, 2004 ; Patel et al, 2012 , 2014 ; Bliss et al, 2016 ; Sandiford et al, 2021 ). Investigations to identify specific markers for CSCs revealed continuous phases of cellular plasticity, which include dedifferentiation of BCC progenitors into BCCs with stem cell–like properties ( Naume et al, 2007 ; Plaks et al, 2015 ; Wang et al, 2017 ; Tjensvoll et al, 2019 ; Lynch-Sutherland et al, 2020 ). Thus, it could be argued that CSCs may be defined as a cellular state that is dependent on the tissue microenvironment.…”

ARID1A loss derepresses human endogenous retrovirus-H to modulate BRD4-dependent transcription

“…ERVs are also involved in many human diseases such as various types of cancer. The abnormally activated ERVs can produce long noncoding RNAs or functional polypeptides 37,[74][75][76][77] , enabling cancer cells to exploit and repurpose developmental pathways to promote malignancy 38 . Of particular note, the reactivated ERVs in cancer are extensively recruited as promoters to drive expression of many oncogenes in a process termed onco-exaptation 78,79 .…”

“…This includes regain the capacity of self-renewal and dramatic alterations in epigenetic landscapes. Interestingly, reactivation of HERVH is also observed in several types of human cancer, such as colorectal carcinomas (CRCs) [34][35][36][37][38][39] , however, a mechanistic insight into this reactivation is lacking and its functional consequence unclear.…”

Endogenous retroviruses in the origins and treatment of cancer

“…Tumorigenesis significantly resembles the corrupt reversion of cells to an earlier developmental state [ 144 ]. As for the preimplantation embryo, TE reactivation is seen in many cancers and can influence tumor genome stability [ 125 , 145 – 150 ].…”

“…Firstly, any cancer therapy intended to target ERV families must consider that each of its copies, including those proximal to key cancer genes, may not behave in the same way. Secondly, as epigenetic repression may be more, or less, enforced on each ERV locus, the accessible complement of ERV regulatory elements is changed, making both tumor suppressor gene downregulation and oncogene upregulation possible at a time and place that alters the course of disease [ 43 , 45 , 127 , 143 , 144 , 152 , 153 ].…”