TY - JOUR
T1 - Flower isoforms promote competitive growth in cancer
AU - Madan, Esha
AU - Pelham, Christopher J.
AU - Nagane, Masaki
AU - Parker, Taylor M.
AU - Canas-Marques, Rita
AU - Fazio, Kimberly
AU - Shaik, Kranti
AU - Yuan, Youzhong
AU - Henriques, Vanessa
AU - Galzerano, Antonio
AU - Yamashita, Tadashi
AU - Pinto, Miguel Alexandre Ferreira
AU - Palma, Antonio M.
AU - Camacho, Denise
AU - Vieira, Ana
AU - Soldini, David
AU - Nakshatri, Harikrishna
AU - Post, Steven R.
AU - Rhiner, Christa
AU - Yamashita, Hiroko
AU - Accardi, Davide
AU - Hansen, Laura A.
AU - Carvalho, Carlos
AU - Beltran, Antonio L.
AU - Kuppusamy, Periannan
AU - Gogna, Rajan
AU - Moreno, Eduardo
N1 - Funding Information:
Acknowledgements This study was supported by ERC, SNSF, Josef Steiner Cancer Research Foundation, Swiss Cancer League and Champalimaud Foundation to E.M.; and Swiss Cancer League, LB692, LB506, Seeds of Science, Winthrop P Rockefeller Cancer Institute and Creighton University startup funds to R.G. We thank K. Polyak for experimental suggestions; J. Billheimer and A. Dhiman for help with analysis; A. Gogna for support; and the MTT platform (R. Tomás), the Histopathology Platform (I. Terras Marques, M. I. Romano, S. Casimiro and S. Dias) and the Rodent platform at the Champalimaud Centre for the Unknown.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system1,2. For example, cell selection in Drosophila uses a cell selection mechanism based on ‘fitness fingerprints’, which allow it to delay ageing3, prevent developmental malformations3,4 and replace old tissues during regeneration5. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins3,4,6. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated6. However, the presence of Flower-Lose isoforms at a cell’s membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed4,6,7. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease8–17. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage18. This would be undesirable for humans because it might make tumours more aggressive19–21. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.
AB - In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system1,2. For example, cell selection in Drosophila uses a cell selection mechanism based on ‘fitness fingerprints’, which allow it to delay ageing3, prevent developmental malformations3,4 and replace old tissues during regeneration5. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins3,4,6. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated6. However, the presence of Flower-Lose isoforms at a cell’s membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed4,6,7. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease8–17. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage18. This would be undesirable for humans because it might make tumours more aggressive19–21. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.
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U2 - 10.1038/s41586-019-1429-3
DO - 10.1038/s41586-019-1429-3
M3 - Article
C2 - 31341286
AN - SCOPUS:85069643042
VL - 572
SP - 260
EP - 264
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7768
ER -