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The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs

Abstract

Triple-negative breast cancer (TNBCs) display lung metastasis tropism. However, the mechanisms underlying this organ-specific pattern remains to be elucidated. We sought to evaluate the utility of blocking extravasation to prevent lung metastasis. To identify potential geminin overexpression-controlled genetic drivers that promote TNBC tumor homing to lungs, we used the differential/suppression subtractive chain (D/SSC) technique. A geminin overexpression-induced lung metastasis gene signature consists of 24 genes was discovered. We validated overexpression of five of these genes (LGR5, HAS2, CDH11, NCAM2, and DSC2) in worsening lung metastasis-free survival in TNBC patients. Our data demonstrate that LGR5-induced β-catenin signaling and stemness in TNBC cells are geminin-overexpression dependent. They also demonstrate for the first-time expression of RSPO2 in mouse lung tissue only and exacerbation of its secretion in the circulation of mice that develop geminin overexpressing/LGR5+-TNBC lung metastasis. We identified a novel extravasation receptor complex, consists of CDH11, CD44v6, c-Met, and AXL on geminin overexpressing/LGR5+-TNBC lung metastatic precursors, inhibition of any of its receptors prevented geminin overexpressing/LGR5+-TNBC lung metastasis. Overall, we propose that geminin overexpression in normal mammary epithelial (HME) cells promotes the generation of TNBC metastatic precursors that home specifically to lungs by upregulating LGR5 expression and promoting stemness, intravasation, and extravasation in these precursors. Circulating levels of RSPO2 and OPN can be diagnostic biomarkers to improve risk stratification of metastatic TNBC to lungs, as well as identifying patients who may benefit from therapy targeting geminin alone or in combination with any member of the newly discovered extravasation receptor complex to minimize TNBC lung metastasis.

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Fig. 1: Molecular signature controlled by GemOE induces TNBC lung metastasis.
Fig. 2: The effect of the D/SSC list on GemOE-induced TNBC lung metastasis.
Fig. 3: The reciprocal effect between geminin and LGR5 exacerbates stemness in TNBC cells.
Fig. 4: Wnt3a cooperates with RSPO2 more than RSPO1 to activate β-catenin-induced stemness in TNBC cells.
Fig. 5: Wnts and RSPO1 are produced locally, while RSPO2 is delivered through the circulation to GemOE-TNBCs.
Fig. 6: Stemness is required but not enough for GemOE/LGR5+-TNBC cells lung metastasis.
Fig. 7: GemOE cells that home to the lungs express CD44/CD44v6, AXL, and c-Met on the surface in an AXL-dependent manner.
Fig. 8: GemOE cells extravasation into the lungs could be blocked by suppressing geminin, CDH11, CD44v6, LGR5, or AXL activities.

Data availability

The data that support the findings of this study are available on request from the corresponding author [WeS].

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Acknowledgements

Wael is Dr. Lawrence & Mrs. Bo Hing Chan Tseu, American Cancer Society Research Scholar.

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In part by grant # RSG-09-275-01 from the American Cancer Society.

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Sami, E., Bogan, D., Molinolo, A. et al. The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs. Cancer Gene Ther 29, 304–325 (2022). https://doi.org/10.1038/s41417-021-00311-x

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