bims-pimaco 2023-12-03 papers

Cell Metab. 2023 Nov 16. pii: S1550-4131(23)00411-4. [Epub ahead of print]

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Cong Jiang, Jing Liu, Shaohui He, Wei Xu, Runzhi Huang, Weijuan Pan, Xiaolong Li, Xiaoming Dai, Jianping Guo, Tao Zhang, Hiroyuki Inuzuka, Ping Wang, John M Asara, Jianru Xiao, Wenyi Wei.

Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.

Keywords: GATOR1; NPRL2; PRMT1; arginine methylation; mTOR; methionine sensing; nutrient sensing

DOI: https://doi.org/10.1016/j.cmet.2023.11.001

Cancer Res. 2023 Nov 28.

One mutation to rule them all: Mutant KRAS controls tumor intrinsic and microenvironment signaling.

Sören Müller, Akshay T Krishnamurty.

In a recent study published in Cancer Discovery, Hsu and colleagues employ an elegant combination of single-cell and bulk RNA-seq experiments from mouse and human colorectal cancer (CRC) samples, patient-derived organoids, 2D in vitro systems, and in vivo validation in genetically engineered CRC mouse models to investigate how mutant KRAS (KRAS*) impacts the tumor microenvironment. They identify a molecular signaling cascade downstream of KRAS* that activates a specific program of lipid-rich CAFs, promoting tumor angiogenesis and progression. These findings may lead to new therapeutic strategies for CRC patients with KRAS*.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3682

Sci Signal. 2023 Nov 28. 16(813): eadg1913

PI3K-C2β limits mTORC1 signaling and angiogenic growth.

Piotr Kobialka, Judith Llena, Nerea Deleyto-Seldas, Margalida Munar-Gelabert, Jose A Dengra, Pilar Villacampa, Alba Albinyà-Pedrós, Laia Muixi, Jorge Andrade, Hielke van Splunder, Ana Angulo-Urarte, Michael Potente, Joaquim Grego-Bessa, Sandra D Castillo, Bart Vanhaesebroeck, Alejo Efeyan, Mariona Graupera.

Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and intracellular vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα and class II PI3K-C2α are essential for vascular development. The class II PI3K-C2β is also abundant in endothelial cells. Using in vivo and in vitro approaches, we found that PI3K-C2β was a critical regulator of blood vessel growth by restricting endothelial mTORC1 signaling. Mice expressing a kinase-inactive form of PI3K-C2β displayed enlarged blood vessels without corresponding changes in endothelial cell proliferation or migration. Instead, inactivation of PI3K-C2β resulted in an increase in the size of endothelial cells, particularly in the sprouting zone of angiogenesis. Mechanistically, we showed that the aberrantly large size of PI3K-C2β mutant endothelial cells was caused by mTORC1 activation, which sustained growth in these cells. Consistently, pharmacological inhibition of mTORC1 with rapamycin normalized vascular morphogenesis in PI3K-C2β mutant mice. Together, these results identify PI3K-C2β as a crucial determinant of endothelial signaling and illustrate the importance of mTORC1 regulation during angiogenic growth.

DOI: https://doi.org/10.1126/scisignal.adg1913

Front Oncol. 2023 ;13 1276654

Cholesterol in colorectal cancer: an essential but tumorigenic precursor?

Xing He, Huanrong Lan, Ketao Jin, Fanlong Liu.

Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.

Keywords: cholesterol; colorectal cancer; metabolism; therapeutic approaches; tumorigenic

DOI: https://doi.org/10.3389/fonc.2023.1276654