The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Pharmacological targeting of the protein synthesis mTOR /4E‐ BP 1 pathway in cancer‐associated fibroblasts abrogates pancreatic tumour chemoresistance
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of α-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential.
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Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
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Environment-mediated drug resistance: A major contributor to minimal residual disease
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Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer
Wolpin, B. M., Hezel, A. F., Abrams, T., Blaszkowsky, L. S., Meyerhardt, J. A., Chan, J. A., Enzinger, P. C., Allen, B., Clark, J. W., Ryan, D. P., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.9514 · Cited by 297
Pasireotide (SOM230): Development, mechanism of action and potential applications
Schmid, H. A. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.09.006 · Cited by 290 · cited 6×
“SOM230 has a high affinity (nanomolar ranges) for all somatostatin receptors, except sst4 (Schmid, 2008).”
BackgroundInfluentialSelf-citationJavle, M. M., Shroff, R. T., Xiong, H., Varadhachary, G. A., Fogelman, D., Reddy, S. A., Davis, D., Zhang, Y., Wolff, R. A., & Abbruzzese, J. L. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-368 · Cited by 170
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Turning foes to friends: targeting cancer-associated fibroblasts
Chen, X., & Song, E. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0004-1 · Cited by 1,879
mTOR signalling and cellular metabolism are mutual determinants in cancer
Mossmann, D., Park, S., & Hall, M. N. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0074-8 · Cited by 1,088
Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer
Wu, F., Yang, J., Liu, J., Wang, Y., Mu, J., Zeng, Q., Deng, S., & Zhou, H. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00641-0 · Cited by 773
Tumor-associated stromal cells as key contributors to the tumor microenvironment
Bussard, K. M., Mutkus, L., Stumpf, K., Gomez-Manzano, C., & Marini, F. C. (2016) · Breast Cancer Research · doi:10.1186/s13058-016-0740-2 · Cited by 746
Fibroblasts in cancer: Unity in heterogeneity
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Metadata
- Authors
- Duluc, C., Moatassim‐Billah, S., Chalabi‐Dchar, M., Perraud, A., Samain, R., Breibach, F., Gayral, M., Cordelier, P., Delisle, M., Bousquet‐Dubouch, M., Tomasini, R., Schmid, H., Mathonnet, M., Pyronnet, S., Martineau, Y., & Bousquet, C.
- Venue
- EMBO Molecular Medicine
- Published
- 2015-04
- Volume
- 7
- Issue
- 6
- Pages
- 735-753
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- OpenAlex
- W2071969343
- Cited by
- 214
- References
- 7
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- gold
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- CoChat. (2026). Citation check: Pharmacological targeting of the protein synthesis mTOR /4E‐ BP 1 pathway in cancer‐associated fibroblasts abrogates pancreatic tumour chemoresistance. https://app.cochat.ai/papers/10.15252/emmm.201404346
- The paper
- Duluc, C., Moatassim‐Billah, S., Chalabi‐Dchar, M., Perraud, A., Samain, R., Breibach, F., Gayral, M., Cordelier, P., Delisle, M., Bousquet‐Dubouch, M., Tomasini, R., Schmid, H., Mathonnet, M., Pyronnet, S., Martineau, Y., & Bousquet, C. (2015). Pharmacological targeting of the protein synthesis mTOR /4E‐ BP 1 pathway in cancer‐associated fibroblasts abrogates pancreatic tumour chemoresistance. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201404346
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