Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Shi, Y., Gao, W., Lytle, N. K, Huang, P., Yuan, X., Dann, A. M, Ridinger-Saison, M., DelGiorno, K. E, Antal, C. E, Liang, G., Atkins, A. R, Erikson, G., Sun, H., Meisenhelder, J., Terenziani, E., Woo, G., Fang, L., Santisakultarm, T. P, Manor, U., Xu, R., Becerra, C. R, Borazanci, E., Von Hoff, D. D, Grandgenett, P. M, Hollingsworth, M. A, Leblanc, M., Umetsu, S. E, Collisson, E. A, Scadeng, M., Lowy, A. M, Donahue, T. R, Reya, T., Downes, M., Evans, R. M, Wahl, G. M, Pawson, T., Tian, R., & Hunter, T. Nature, 569(7754):131–135, 2019.
Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring [link]Paper  doi  abstract   bibtex   
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3–7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8–10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
@article{Shi2019,
  abstract = {Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3–7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8–10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.},
  author = {Shi, Yu and Gao, Weina and Lytle, Nikki K and Huang, Peiwu and Yuan, Xiao and Dann, Amanda M and Ridinger-Saison, Maya and DelGiorno, Kathleen E and Antal, Corina E and Liang, Gaoyang and Atkins, Annette R and Erikson, Galina and Sun, Huaiyu and Meisenhelder, Jill and Terenziani, Elena and Woo, Gyunghwi and Fang, Linjing and Santisakultarm, Thom P and Manor, Uri and Xu, Ruilian and Becerra, Carlos R and Borazanci, Erkut and {Von Hoff}, Daniel D and Grandgenett, Paul M and Hollingsworth, Michael A and Leblanc, Mathias and Umetsu, Sarah E and Collisson, Eric A and Scadeng, Miriam and Lowy, Andrew M and Donahue, Timothy R and Reya, Tannishtha and Downes, Michael and Evans, Ronald M and Wahl, Geoffrey M and Pawson, Tony and Tian, Ruijun and Hunter, Tony},
  doi = {10.1038/s41586-019-1130-6},
  issn = {1476-4687},
  journal = {Nature},
  number = {7754},
  pages = {131--135},
  title = {{Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring}},
  url = {https://doi.org/10.1038/s41586-019-1130-6},
  volume = {569},
  year = {2019}
}
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