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. 2020 Jun 16;9(1):1773204.
doi: 10.1080/2162402X.2020.1773204.

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells

Luis Augusto Aguirre  1   2 , Karla Montalbán-Hernández  1   2 , José Avendaño-Ortiz  1   2   3 , Elvira Marín  1   2 , Roberto Lozano  1   2 , Víctor Toledano  1   2   3 , Laura Sánchez-Maroto  1   2 , Verónica Terrón  1   2 , Jaime Valentín  1   2 , Elisa Pulido  1   2 , José Carlos Casalvilla  1   2 , Carolina Rubio  1   2 , Luke Diekhorst  4 , Fernando Laso-García  4 , Carlos Del Fresno  5 , Ana Collazo-Lorduy  6 , Beatriz Jiménez-Munarriz  6 , Paloma Gómez-Campelo  1   2 , Emilio Llanos-González  1   2 , María Fernández-Velasco  1   7 , Carlos Rodríguez-Antolín  8 , Rebeca Pérez de Diego  1   9 , Ramón Cantero-Cid  1   2 , Enrique Hernádez-Jimenez  1   2 , Enrique Álvarez  1   2 , Rocío Rosas  8 , Blanca Dies López-Ayllón  8   10   11 , Javier de Castro  8 , Stefanie K Wculek  5 , Carolina Cubillos-Zapata  1   2   3 , Inmaculada Ibáñez de Cáceres  8 , Prudencio Díaz-Agero  12 , María Gutiérrez Fernández  4 , María Paz de Miguel  13 , David Sancho  5 , Leon Schulte  14 , Rosario Perona  8   10   11 , Cristóbal Belda-Iniesta  6 , Lisardo Boscá  1   7   10 , Eduardo López-Collazo  1   2   3
Affiliations

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells

Luis Augusto Aguirre et al. Oncoimmunology. .

Abstract

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.

Keywords: CD36; Cancer stem cells; lung cancer; metastasis; monocytes/macrophages.

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Figures

Figure 1.
Figure 1.
Co-culture in vitro of cancer stem cells and human monocytes generates hybrid cells.
Figure 2.
Figure 2.
Fused-cells exhibit a patent entity.
Figure 3.
Figure 3.
Fusion process efficacy depends on both the regulation of CD36 expression by CSCs and microenvironmental lipids fluctuations, and the oxidative status and M2-phenotype of MΦs.
Figure 4.
Figure 4.
THCs show migration and proliferation capabilities both in vitro and in vivo.
Figure 5.
Figure 5.
THCs downregulate in vitro immune response.
Figure 6.
Figure 6.
THCs specific markers signatures in patients with lung cancer.
See this image and copyright information in PMC

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