bims-pimaco 2021-10-17 papers

Cancers (Basel). 2021 Oct 01. pii: 4959. [Epub ahead of print]13(19):

Superior Overall Survival in Patients with Colorectal Cancer, Regular Aspirin Use, and Combined Wild-Type PIK3CA and KRAS-Mutated Tumors.

Leonie Gebauer, Andrea Nist, Marco Mernberger, Thorsten Stiewe, Roland Moll, Kathleen Stabla, Uwe Klinge, Elisabeth Mack, Cornelia Brendel, Andreas Neubauer.

The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38; 95% CI = 0.17-0.87; p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.

Keywords: KRAS; PIK3CA; aspirin use; colorectal cancer

DOI: https://doi.org/10.3390/cancers13194959

J Biol Chem. 2021 Oct 08. pii: S0021-9258(21)01096-6. [Epub ahead of print] 101291

Tyrosine Phosphorylation of DEPTOR Functions as a Molecular Switch to Activate mTOR Signaling.

Laurence M Gagné, Nadine Morin, Noémie Lavoie, Nicolas Bisson, Jean-Philippe Lambert, Frédérick A Mallette, Marc-Étienne Huot.

Metabolic dysfunction is a major driver of tumorigenesis. The serine/threonine kinase mTOR constitutes a key central regulator of metabolic pathways promoting cancer cell proliferation and survival. mTOR activity is regulated by metabolic sensors as well as by numerous factors comprising the PTEN/PI3K/AKT canonical pathway, which are often mutated in cancer. However, some cancers displaying constitutively active mTOR do not carry alterations within this canonical pathway, suggesting alternative modes of mTOR regulation. Since DEPTOR, an endogenous inhibitor of mTOR, was previously found to modulate both mTOR complexe 1 and 2, we investigated the different post-transltionnal modification that could affect its inhibitory function. We found that tyrosine 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (Spleen tyrosine kinase) as a kinase involved in DEPTOR tyrosine 289 phosphorylation in an ephrin (EPH) receptor-dependent manner. Altogether, our work reveals that phosphorylation of tyrosine 289 of DEPTOR represents a novel molecular switch involved in the regulation of both mTORC1 and mTORC2.

Keywords: DEPTOR; EPHB2; mTOR; tyrosine phosphorylation

DOI: https://doi.org/10.1016/j.jbc.2021.101291

Trends Biochem Sci. 2021 Nov;pii: S0968-0004(21)00108-0. [Epub ahead of print]46(11): 878-888

PI3K functions as a hub in mechanotransduction.

M Di-Luoffo, Z Ben-Meriem, P Lefebvre, M Delarue, J Guillermet-Guibert.

Mammalian cells integrate different types of stimuli that govern their fate. These stimuli encompass biochemical as well as biomechanical cues (shear, tensile, and compressive stresses) that are usually studied separately. The phosphatidylinositol 3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. Recent evidence in cancer research demonstrates that these enzymes are essential in mechanotransduction. Despite this, the importance of the integration of biomechanical cues and PI3K-driven biochemical signals is underestimated. In this opinion article, we make the hypothesis that modeling of biomechanical cues is critical to understand PI3K oncogenicity. We also identify known/missing knowledge in terms of isoform specificity and molecular pathways of activation, knowledge that is needed for clinical applications.

Keywords: PI3K; cell signaling; compression; mechanotransduction; shear stress; tension

DOI: https://doi.org/10.1016/j.tibs.2021.05.005

Genome Med. 2021 Oct 14. 13(1): 165

Integrating thousands of PTEN variant activity and abundance measurements reveals variant subgroups and new dominant negatives in cancers.

Kenneth A Matreyek, Jason J Stephany, Ethan Ahler, Douglas M Fowler.

BACKGROUND: PTEN is a multi-functional tumor suppressor protein regulating cell growth, immune signaling, neuronal function, and genome stability. Experimental characterization can help guide the clinical interpretation of the thousands of germline or somatic PTEN variants observed in patients. Two large-scale mutational datasets, one for PTEN variant intracellular abundance encompassing 4112 missense variants and one for lipid phosphatase activity encompassing 7244 variants, were recently published. The combined information from these datasets can reveal variant-specific phenotypes that may underlie various clinical presentations, but this has not been comprehensively examined, particularly for somatic PTEN variants observed in cancers.
METHODS: Here, we add to these efforts by measuring the intracellular abundance of 764 new PTEN variants and refining abundance measurements for 3351 previously studied variants. We use this expanded and refined PTEN abundance dataset to explore the mutational patterns governing PTEN intracellular abundance, and then incorporate the phosphatase activity data to subdivide PTEN variants into four functionally distinct groups.
RESULTS: This analysis revealed a set of highly abundant but lipid phosphatase defective variants that could act in a dominant-negative fashion to suppress PTEN activity. Two of these variants were, indeed, capable of dysregulating Akt signaling in cells harboring a WT PTEN allele. Both variants were observed in multiple breast or uterine tumors, demonstrating the disease relevance of these high abundance, inactive variants.
CONCLUSIONS: We show that multidimensional, large-scale variant functional data, when paired with public cancer genomics datasets and follow-up assays, can improve understanding of uncharacterized cancer-associated variants, and provide better insights into how they contribute to oncogenesis.

Keywords: Cancer genomics; Dominant-negative; Multiplex assays of variant effect; PTEN; Protein variants; VAMP-seq

DOI: https://doi.org/10.1186/s13073-021-00984-x