bims-pimaco 2023-11-26 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–11–26
five papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology.
Using Drosophila melanogaster to Dissect the Roles of the mTOR Signaling Pathway in Cell Growth.
Source, co-occurrence, and prognostic value of PTEN mutations or loss in colorectal cancer.
Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRASG12D Inhibitor MRTX1133.
Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2.

Nat Rev Mol Cell Biol. 2023 Nov 24.

Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology.

Carmine Settembre, Rushika M Perera.

Every cell must satisfy basic requirements for nutrient sensing, utilization and recycling through macromolecular breakdown to coordinate programmes for growth, repair and stress adaptation. The lysosome orchestrates these key functions through the synchronised interplay between hydrolytic enzymes, nutrient transporters and signalling factors, which together enable metabolic coordination with other organelles and regulation of specific gene expression programmes. In this Review, we discuss recent findings on lysosome-dependent signalling pathways, focusing on how the lysosome senses nutrient availability through its physical and functional association with mechanistic target of rapamycin complex 1 (mTORC1) and how, in response, the microphthalmia/transcription factor E (MiT/TFE) transcription factors exert feedback regulation on lysosome biogenesis. We also highlight the emerging interactions of lysosomes with other organelles, which contribute to cellular homeostasis. Lastly, we discuss how lysosome dysfunction contributes to diverse disease pathologies and how inherited mutations that compromise lysosomal hydrolysis, transport or signalling components lead to multi-organ disorders with severe metabolic and neurological impact. A deeper comprehension of lysosomal composition and function, at both the cellular and organismal level, may uncover fundamental insights into human physiology and disease.

DOI: https://doi.org/10.1038/s41580-023-00676-x
Cells. 2023 Nov 14. pii: 2622. [Epub ahead of print]12(22):

Using Drosophila melanogaster to Dissect the Roles of the mTOR Signaling Pathway in Cell Growth.

Anna Frappaolo, Maria Grazia Giansanti.

  The evolutionarily conserved target of rapamycin (TOR) serine/threonine kinase controls eukaryotic cell growth, metabolism and survival by integrating signals from the nutritional status and growth factors. TOR is the catalytic subunit of two distinct functional multiprotein complexes termed mTORC1 (mechanistic target of rapamycin complex 1) and mTORC2, which phosphorylate a different set of substrates and display different physiological functions. Dysregulation of TOR signaling has been involved in the development and progression of several disease states including cancer and diabetes. Here, we highlight how genetic and biochemical studies in the model system Drosophila melanogaster have been crucial to identify the mTORC1 and mTORC2 signaling components and to dissect their function in cellular growth, in strict coordination with insulin signaling. In addition, we review new findings that involve Drosophila Golgi phosphoprotein 3 in regulating organ growth via Rheb-mediated activation of mTORC1 in line with an emerging role for the Golgi as a major hub for mTORC1 signaling.

Keywords:  Drosophila; GOLPH3; Golgi; mTOR signaling

DOI:  https://doi.org/10.3390/cells12222622
NPJ Genom Med. 2023 Nov 24. 8(1): 40

Source, co-occurrence, and prognostic value of PTEN mutations or loss in colorectal cancer.

Ilya G Serebriiskii, Valerii A Pavlov, Grigorii V Andrianov, Samuel Litwin, Stanley Basickes, Justin Y Newberg, Garrett M Frampton, Joshua E Meyer, Erica A Golemis.

Somatic PTEN mutations are common and have driver function in some cancer types. However, in colorectal cancers (CRCs), somatic PTEN-inactivating mutations occur at a low frequency (~8-9%), and whether these mutations are actively selected and promote tumor aggressiveness has been controversial. Analysis of genomic data from ~53,000 CRCs indicates that hotspot mutation patterns in PTEN partially reflect DNA-dependent selection pressures, but also suggests a strong selection pressure based on protein function. In microsatellite stable (MSS) tumors, PTEN alterations co-occur with mutations activating BRAF or PI3K, or with TP53 deletions, but not in CRC with microsatellite instability (MSI). Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration.

DOI: https://doi.org/10.1038/s41525-023-00384-7
J Proteome Res. 2023 Nov 20.

Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRASG12D Inhibitor MRTX1133.

Benjamin C Orsburn.

  Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRASG12D mutant proteins, which is one of the main drivers of pancreatic cancer. To better understand the mechanism of action of this compound, I performed both proteomics and metabolomics on four KRASG12D mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single-cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1498 single cells were analyzed. From these cells, 3140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.

Keywords:  KRAS; MRTX1133; metabolomics; proteomics; single-cell proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.3c00212
Sci Adv. 2023 Nov 24. 9(47): eadh9673

Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2.

Gabriele Colozza, Heetak Lee, Alessandra Merenda, Szu-Hsien Sam Wu, Andrea Català-Bordes, Tomasz W Radaszkiewicz, Ingrid Jordens, Ji-Hyun Lee, Aileen-Diane Bamford, Fiona Farnhammer, Teck Yew Low, Madelon M Maurice, Vítězslav Bryja, Jihoon Kim, Bon-Kyoung Koo.

The mammalian intestine is one of the most rapidly self-renewing tissues, driven by stem cells residing at the crypt bottom. Paneth cells form a major element of the niche microenvironment providing various growth factors to orchestrate intestinal stem cell homeostasis, such as Wnt3. Different Wnt ligands can selectively activate β-catenin-dependent (canonical) or -independent (noncanonical) signaling. Here, we report that the Dishevelled-associated activator of morphogenesis 1 (Daam1) and its paralogue Daam2 asymmetrically regulate canonical and noncanonical Wnt (Wnt/PCP) signaling. Daam1/2 interacts with the Wnt inhibitor RNF43, and Daam1/2 double knockout stimulates canonical Wnt signaling by preventing RNF43-dependent degradation of the Wnt receptor, Frizzled (Fzd). Single-cell RNA sequencing analysis revealed that Paneth cell differentiation is impaired by Daam1/2 depletion because of defective Wnt/PCP signaling. Together, we identified Daam1/2 as an unexpected hub molecule coordinating both canonical and noncanonical Wnt, which is fundamental for specifying an adequate number of Paneth cells.

DOI: https://doi.org/10.1126/sciadv.adh9673