Stress granules are not present in Kras mutant cancers and do not control tumor growth

• Published in: EMBO reports 2024-11, Vol.25 (11), p.4693-4707
• Main Authors: Libert, Maxime, Quiquempoix, Sophie, Fain, Jean S, Pyr dit Ruys, Sébastien, Haidar, Malak, Wulleman, Margaux, Herinckx, Gaëtan, Vertommen, Didier, Bouchart, Christelle, Arsenijevic, Tatjana, Van Laethem, Jean-Luc, Jacquemin, Patrick
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Carcinogenesis - genetics; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation; EMBO03; EMBO36; EMBO37; Humans; Life Sciences; Mice; Mutation; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Stress Granules - genetics; Stress Granules - metabolism
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00284-6

Stress granules (SG) are membraneless ribonucleoprotein-based cytoplasmic organelles that assemble in response to stress. Their formation is often associated with an almost global suppression of translation, and the aberrant assembly or disassembly of these granules has pathological implications in neurodegeneration and cancer. In cancer, and particularly in the presence of oncogenic KRAS mutations, in vivo studies concluded that SG increase the resistance of cancer cells to stress. Hence, SG have recently been considered a promising target for therapy. Here, starting from our observations that genes coding for SG proteins are stimulated during development of pancreatic ductal adenocarcinoma, we analyze the formation of SG during tumorigenesis. We resort to in vitro, in vivo and in silico approaches, using mouse models, human samples and human data. Our analyses do not support that SG are formed during tumorigenesis of KRAS-driven cancers, at least that their presence is not universal, leading us to propose that caution is required before considering SG as therapeutic targets. Synopsis Despite higher levels of mRNA encoding SG proteins during pancreatic tumorigenesis, this study finds no SG formation in Kras-driven cancers. This suggests that SG may not be a universal therapeutic cancer target. Stress granules (SG) were not detected in Kras-driven lesions in mouse models or in human PDAC samples. The protein interactome of G3BP does not indicate a role for G3BP related to SG formation. SG are not universally present or relevant in Kras-mutant cancers. Caution is warranted before pursuing SG as a cancer therapeutic target in Kras-mutant cancers. Despite higher levels of mRNA encoding SG proteins during pancreatic tumorigenesis, this study finds no SG formation in Kras-driven cancers. This suggests that SG may not be a universal therapeutic cancer target.