bims-pimaco 2023-10-01 papers

Issue of 2023‒10‒01
eight papers selected by
Lucas B. Zeiger, Beatson Institute for Cancer Research

Biomolecules. 2023 Aug 24. pii: 1297. [Epub ahead of print]13(9):

Regulation of Phosphoinositide Signaling by Scaffolds at Cytoplasmic Membranes.

Tianmu Wen, Narendra Thapa, Vincent L Cryns, Richard A Anderson.

Cytoplasmic phosphoinositides (PI) are critical regulators of the membrane-cytosol interface that control a myriad of cellular functions despite their low abundance among phospholipids. The metabolic cycle that generates different PI species is crucial to their regulatory role, controlling membrane dynamics, vesicular trafficking, signal transduction, and other key cellular events. The synthesis of phosphatidylinositol (3,4,5)-triphosphate (PI3,4,5P3) in the cytoplamic PI3K/Akt pathway is central to the life and death of a cell. This review will focus on the emerging evidence that scaffold proteins regulate the PI3K/Akt pathway in distinct membrane structures in response to diverse stimuli, challenging the belief that the plasma membrane is the predominant site for PI3k/Akt signaling. In addition, we will discuss how PIs regulate the recruitment of specific scaffolding complexes to membrane structures to coordinate vesicle formation, fusion, and reformation during autophagy as well as a novel lysosome repair pathway.

Keywords: PI3K-Akt pathway; autophagy; lysosome; phosphoinositide; scaffolding protein

DOI: https://doi.org/10.3390/biom13091297

Anticancer Res. 2023 Oct;43(10): 4341-4348

Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRASG12D Inhibitor, in Colorectal Cancer Treatment.

Masahiro Kataoka, Masato Kitazawa, Satoshi Nakamura, Makoto Koyama, Yuta Yamamoto, Satoru Miyazaki, Nao Hondo, Hirokazu Tanaka, Yuji Soejima.

BACKGROUND/AIM: Kirsten Rat Sarcoma viral oncogene homolog (KRAS) has remained undruggable for decades. KRAS has predominantly been used to evaluate the applicability of anti-Epidermal Growth Factor Receptor (EGFR) antibody drugs. However, various KRAS inhibitors have recently emerged. Unfortunately, KRAS inhibitors have not been effective against colorectal cancer. Therefore, this study aimed to determine the effects of MRTX1133, a novel KRASG12D inhibitor, in combination with an anti-EGFR antibody, cetuximab, on signal transduction and cell proliferation.MATERIALS AND METHODS: The KRASG12D-mutated LS513 and KRAS wild-type CACO-2 human colon cancer cell lines were utilized. The KRASG12D mutation was stably transduced into the CACO-2 cells using a retrovirus. We evaluated the effects of the drugs using the CCK-8 assay and assessed the activity of proteins related to the MAPK pathway using western blotting.
RESULTS: We demonstrated that the administration of MRTX1133, a novel KRASG12D inhibitor, to KRASG12D-mutated colorectal cancer cells led to feedback activation of the ERK pathway via EGFR activation, inducing drug resistance. Intriguingly, when MRTX1133 was used in combination with cetuximab, KRASG12D-mutant colorectal cancer growth was effectively inhibited, both in vitro and in vivo.
CONCLUSION: The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRASG12D mutation. KRASG12D is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients.

Keywords: Colorectal cancer; EGFR; G12D; KRAS; MRTX1133

DOI: https://doi.org/10.21873/anticanres.16629

Comput Biol Med. 2023 Sep 09. pii: S0010-4825(23)00920-4. [Epub ahead of print]166 107455

Cooperativity and oscillations: Regulatory mechanisms of K-Ras nanoclusters.

Manuel Jurado, Antonio Zorzano, Oscar Castaño.

K-Ras nanoclusters (NCs) concentrate all required molecules belonging to the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway in a small area where signaling events take place, increasing efficiency and speciﬁcity of signaling. Such nanostructures are characterized by controlled sizes and lifetimes distributions, but there is a poor understanding of the mechanisms involved in their dynamics of growth/decay. Here, a minimum computational model is presented to analyze the behavior of K-Ras NCs as cooperative dynamic structures that self-regulate their growth and decay according to their size. Indeed, the proposed model reveals that the growth and the local production of a K-Ras nanocluster depend positively on its actual size, whilst its lifetime is inversely proportional to the root of its size. The cooperative binding between the structural constituents of the NC (K-Ras proteins) induces oscillations in the size distributions of K-Ras NCs allowing them to range within controlled values, regulating the growth/decay dynamics of these NCs. Thereby, the size of a K-Ras NC is proposed as a key factor to regulate cell signaling, opening a range of possibilities to develop strategies for use in chronic diseases and cancer.

Keywords: Cancer; Cell signaling; Computational model; Cooperativity; MAPK pathway; Ras nanocluster

DOI: https://doi.org/10.1016/j.compbiomed.2023.107455

Cancer Res Commun. 2023 Sep 26. 3(9): 1940-1951

Fusobacterium nucleatum Load Correlates with KRAS Mutation and Sessile Serrated Pathogenesis in Colorectal Adenocarcinoma.

Koki Takeda, Minoru Koi, Yoshiki Okita, Sija Sajibu, Temitope O Keku, John M Carethers.

SIGNIFICANCE: The authors demonstrated that Fn is enriched in colorectal cancers exhibiting the SSP phenotype, and in colorectal cancers carrying KRAS mutations. Fn infection should be considered as a candidate risk factor specific to colorectal cancers with the SSP phenotype and with KRAS mutations.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0179

Cancer Discov. 2023 Sep 28.

Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression.

Wen-Hao Hsu, Kyle A LaBella, Yiyun Lin, Ping Xu, Rumi Lee, Cheng-En Hsieh, Lei Yang, Ashley Zhou, Jonathan M Blecher, Chang-Jiun Wu, Kangyu Lin, Xiaoying Shang, Shan Jiang, Denise J Spring, Yan Xia, Peiwen Chen, John Paul Shen, Scott Kopetz, Ronald A DePinho.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* suppresses anti-tumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAFs) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) which upregulates the expression of the pro-adipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce vascular endothelial growth factor A (VEGFA) to spur angiogenesis. In KRAS*-driven CRC mouse models, genetic or pharmacological neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human CRC, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven CRC.

DOI: https://doi.org/10.1158/2159-8290.CD-22-1467

Nat Cell Biol. 2023 Sep 25.

Iron drives anabolic metabolism through active histone demethylation and mTORC1.

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

DOI: https://doi.org/10.1038/s41556-023-01225-6