Cell–cell fusion of mesenchymal cells with distinct differentiations triggers genomic and transcriptomic remodelling toward tumour aggressiveness

Abstract

Cell–cell fusion is a physiological process that is hijacked during oncogenesis and promotes tumour evolution. The main known impact of cell fusion is to promote the formation of metastatic hybrid cells following fusion between mobile leucocytes and proliferating tumour cells. We show here that cell fusion between immortalized myoblasts and transformed fibroblasts, through genomic instability and expression of a specific transcriptomic profile, leads to emergence of hybrid cells acquiring dissemination properties. This is associated with acquisition of clonogenic ability by fused cells. In addition, by inheriting parental properties, hybrid tumours were found to mimic the histological characteristics of a specific histotype of sarcomas: undifferentiated pleomorphic sarcomas with incomplete muscular differentiation. This finding suggests that cell fusion, as macroevolution event, favours specific sarcoma development according to the differentiation lineage of parent cells.

Cell–Cell Fusion and the Roads to Novel Properties of Tumor Hybrid Cells

“…Likewise, a substantial shift in the phenotypes of MDA-MB-231 × SUM159PT hybrids at early (2) and extended (10) passages was observed, which was further consistent with the selection of a fit subpopulation of hybrid cells and additional diversification [16]. Hybrid clones derived from human breast epithelial cells and human breast cancer cells possessed a unique mean chromosomal number [64,113], which is in accordance with recent data of Delespaul et al and Lartigue and colleagues who also showed that mesenchymal tumor hybrid clones exhibited a unique chromosomal content [114][115][116]. In this connection, it should be kept in mind that PSHP/AKE does not stop at a certain time point, e.g., after 10 or 15 divisions.…”

Hybrid Formation and Fusion of Cancer Cells In Vitro and In Vivo

“…Similar findings were reported for hybrid cells that were derived from immortalized myoblasts and transformed fibroblasts by exhibiting clonogenic ability and dissemination properties [31]. Moreover, hybrid tumors were found to mimic the histological characteristics of undifferentiated pleomorphic sarcomas with incomplete muscular differentiation, suggesting that cell fusion might favor specific sarcoma development according to the differentiation lineage of parent cells [31].…”

“…Several studies using genetically modified cancer cells and transgenic mouse models have revealed cancer cell fusion among themselves (homotypic fusion) or with other cell types in the tumor microenvironment, such as macrophages, CAFs, or MSC (heterotypic fusion) [31,32,73,123,125,198,[204][205][206].…”

“…Markers to identify cancer cell fusion and to isolate cancer hybrid cells include resistance to different antibiotics, or the co-expression of two different fluorescent reporter proteins [31,32,73,123,128,129,133,134,137,138,[140][141][142][143][144][145][147][148][149][150][151][152]154,155,158,161,162,164,167,169,[171][172][173][174]178], or the use of hypoxanthine, aminopterin, or thymidine (HAT) medium [125,160,173,175], respectively.…”

“…Some of them remain in a stable multinucleated or so-called heterokaryon state, such as syncytiotrophoblasts, multinucleated muscle fibers, and osteoclasts [10][11][12][13][14][15][16][17]19,[22][23][24]. In contrast, some bi-or multinucleated cells can also give rise to mononucleated daughter cells via a process that has been independently from the other named the "heterokaryon-to-synkaryon transition" (HST) [25] or synonymously "ploidy reductions" (PR) [26][27][28][29] and which has been observed in several cell types, including hepatic cells [26][27][28], hematopoietic cells [29], epithelial cells [30], and fibroblasts [31,32]. In accordance with the not yet fully understood process of cell fusion, the phenomenon of HST/PR also remains ambiguous.…”