{"id":16694,"date":"2021-05-07T10:29:00","date_gmt":"2021-05-07T08:29:00","guid":{"rendered":"https:\/\/idibell.cat\/en\/?post_type=agenda&p=16694"},"modified":"2021-06-01T08:50:31","modified_gmt":"2021-06-01T06:50:31","slug":"idibellseminars-tumor-cell-intrinsic-and-extrinsic-roles-of-the-integrated-stress-response-in-malignant-progression-and-metastasis","status":"publish","type":"agenda","link":"https:\/\/idibell.cat\/en\/agenda\/idibellseminars-tumor-cell-intrinsic-and-extrinsic-roles-of-the-integrated-stress-response-in-malignant-progression-and-metastasis\/","title":{"rendered":"#IDIBELLseminars: Tumor cell-intrinsic and -extrinsic roles of the integrated stress response in malignant progression and metastasis"},"content":{"rendered":"

Constantinos Koumenis<\/strong>
\nPerelman School of Medicine, University of Pennsylvania, PA, USA<\/p>\n

Tumor progression and metastasis is associated with the development of a range of microenvironmental stresses including hypoxia, nutrient limitation, and inflammation as well as intrinsic stresses, such as those imposed by oncogenic activation. When confronted with such stress, cells elicit adaptive pro-survival responses, including the integrated stress response (ISR). The ISR refers to a conserved and coordinated pathway comprised of four kinases that converge on phosphorylation of the eukaryotic translation initiation factor eIF2\u03b1. ISR activation via eIF2\u03b1 phosphorylation conserves resources by downregulating global, cap-dependent translation while promoting translational upregulation of specific mRNAs via features in the 5\u2019-untranslated region. The best-studied of these codes for the ATF4 transcription factor, which regulates expression of mRNAs involved in amino acid transport and biosynthesis, redox balance, angiogenesis and autophagy. Activation of the ISR has been reported in many human tumors including breast and prostate cancer, lymphomas, sarcomas, melanomas, etc.
\nIn the first part of my talk, I will present some of our published work supporting a critical role of ATF4 in promoting tumor cell survival in the context of dysregulation of the proto-oncogene c-Myc. I will also outline an emerging role of ATF4 as a \u201crheostat\u201d of Myc\u2019s potent upregulation od translational activity and metabolic reprogramming, thereby enabling Myc-dependent tumorigenesis. Although the pro-tumorigenic role of the ISR in a tumor cell-intrinsic manner has been established, its role in cell-extrinsic processes remains unexplored. In the second part of my talk, I will present unpublished data from my lab, where using novel conditional knockout ATF4 mouse models, we show that global, or fibroblast (FB)-specific loss of host ATF4 results in abnormal tumor vascularization and a pronounced tumor growth delay in syngeneic melanoma and pancreatic tumor models. We find that loss of host ATF4 results in attenuation of cancer associated fibroblast (CAF) activation and that ATF4 directly regulates expression of the collagen genes as well as biosynthesis of glycine and proline, the major amino acids comprising collagen fibers.
\nTogether, the tumor-intrinsic and -extrinsic roles of the ISR in cancer progression and metastasis make a strong case for targeting components of these pathways as effective anti-tumor strategies.<\/p>\n

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