Pregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasion.
Melanoma is the most common cancer diagnosed in pregnant women and an aggressive course with poorer outcomes is commonly described during pregnancy or shortly after childbirth. The underlying mechanisms for this are not understood. Here, we report that melanoma migration, invasiveness and progression are promoted by Pregnancy-Associated Plasma Protein-A (PAPPA), a pregnancy-associated metalloproteinase produced by the placenta that increases the bioavailability of IGF1 by cleaving it from a circulating complex formed with IGFBP4. We show that PAPPA is widely expressed by metastatic melanoma tumors and is elevated in melanoma cells exhibiting mesenchymal, invasive and label-retaining phenotypes. Notably, inhibition of PAPPA significantly reduced invasion and migration of melanoma cells in vitro and in vivo within the embryonic chicken neural tube. PAPPA-enriched pregnancy serum treatment enhanced melanoma motility in vitro. Furthermore, we report that IGF1 can induce the phenotypic and functional effects of epithelial-to-mesenchymal transition (EMT) in melanoma cells. In this study, we establish a clear relationship between a pregnancy-associated protein PAPPA, melanoma and functional effects mediated through IGF1 that provides a plausible mechanism for accelerated melanoma progression during pregnancy. This opens the possibility of targeting the PAPPA/IGF1 axis therapeutically.
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.|Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.|Department of Medicine, University of Melbourne, VIC, Australia.
Prashanth
P
Prithviraj
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.
Matthew
M
Anaka
Department of Anatomy and Neuroscience, University of Melbourne, VIC, Australia.
Sonja J
SJ
McKeown
Mercy Hospital for Women, Heidelberg, VIC, Australia.
Michael
M
Permezel
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.|Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.
Marzena
M
Walkiewicz
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.|Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.|Department of Medicine, University of Melbourne, VIC, Australia.|School of Cancer Medicine, La Trobe University, VIC, Australia.
Jonathan
J
Cebon
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.|Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.|Department of Medicine, University of Melbourne, VIC, Australia.|School of Cancer Medicine, La Trobe University, VIC, Australia.
Andreas
A
Behren
Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, Australia.|Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, VIC, Australia.|Department of Medicine, University of Melbourne, VIC, Australia.|School of Cancer Medicine, La Trobe University, VIC, Australia.
Aparna
A
Jayachandran
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002642:Chick Embryo; D018920:Coculture Techniques; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
C583557:IGF1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I; D011266:Pregnancy-Associated Plasma Protein-A
EMT; PAPPA; invasion; melanoma; pregnancy