bims-pimaco 2023-12-17 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2023–12–17
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

Epinephrine inhibits PI3Kα via the Hippo kinases.
An oncogenic phenoscape of colonic stem cell polarization.
Cells use multiple mechanisms for cell-cycle arrest upon withdrawal of individual amino acids.
Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation.
Revolutionizing KRAS p.G12C therapy in metastatic colorectal cancer: The triumph of dual inhibition.
Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses.
MYC protein helps cancer to take its vitamins.

Cell Rep. 2023 Dec 04. pii: S2211-1247(23)01547-4. [Epub ahead of print]42(12): 113535

Epinephrine inhibits PI3Kα via the Hippo kinases.

Ting-Yu Lin, Shakti Ramsamooj, Tiffany Perrier, Katarina Liberatore, Louise Lantier, Neil Vasan, Kannan Karukurichi, Seo-Kyoung Hwang, Edward A Kesicki, Edward R Kastenhuber, Thorsten Wiederhold, Tomer M Yaron, Emily M Huntsman, Mengmeng Zhu, Yilun Ma, Marcia N Paddock, Guoan Zhang, Benjamin D Hopkins, Owen McGuinness, Robert E Schwartz, Baran A Ersoy, Lewis C Cantley, Jared L Johnson, Marcus D Goncalves.

  The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.

Keywords:  CP: Metabolism; CP: Molecular biology; Hippo kinases; PI3K signaling; epinephrine signaling; glucose metabolism; glycogen metabolism; insulin sensitivity; liver

DOI:  https://doi.org/10.1016/j.celrep.2023.113535
Cell. 2023 Dec 07. pii: S0092-8674(23)01221-7. [Epub ahead of print]186(25): 5554-5568.e18

An oncogenic phenoscape of colonic stem cell polarization.

Xiao Qin, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Jeroen Claus, Christopher J Tape.

  Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU)+ revival colonic stem cells (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRASG12D or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12D collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.

Keywords:  CRC; cell plasticity; cell-cell signaling; cell-fate polarization; colonic stem cell; colorectal cancer; cue-signal-response; organoid; single-cell analysis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2023.11.004
Cell Rep. 2023 Dec 07. pii: S2211-1247(23)01551-6. [Epub ahead of print]42(12): 113539

Cells use multiple mechanisms for cell-cycle arrest upon withdrawal of individual amino acids.

Yao Rong, Alicia M Darnell, Kiera M Sapp, Matthew G Vander Heiden, Sabrina L Spencer.

  Amino acids are required for cell growth and proliferation, but it remains unclear when and how amino acid availability impinges on the proliferation-quiescence decision. Here, we used time-lapse microscopy and single-cell tracking of cyclin-dependent kinase 2 (CDK2) activity to assess the response of individual cells to withdrawal of single amino acids and found strikingly different cell-cycle effects depending on the amino acid. For example, upon leucine withdrawal, MCF10A cells complete two cell cycles and then enter a CDK2-low quiescence, whereas lysine withdrawal causes immediate cell-cycle stalling. Methionine withdrawal triggers a restriction point phenotype similar to serum starvation or Mek inhibition: upon methionine withdrawal, cells complete their current cell cycle and enter a CDK2-low quiescence after mitosis. Modulation of restriction point regulators p21/p27 or cyclin D1 enables short-term rescue of proliferation under methionine and leucine withdrawal, and to a lesser extent lysine withdrawal, revealing a checkpoint connecting nutrient signaling to cell-cycle entry.

Keywords:  CDK2; CP: Cell biology; amino acid withdrawal; cyclin D1; leucine; lysine; methionine; p21; p27; proliferation-quiescence decision; restriction point

DOI:  https://doi.org/10.1016/j.celrep.2023.113539
Exp Cell Res. 2023 Dec 08. pii: S0014-4827(23)00423-8. [Epub ahead of print] 113872

Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation.

Debojyoti De, Ginia Ghosh, Parimal Karmakar.

  Autophagy is involved in the entirety of cellular survival, homeostasis and death which becomes more self-evident when its dysregulation is implicated in several pathological conditions. PTEN positively regulates autophagy and like other proteins undergo post-translational modifications. It is crucial to investigate the relationship between PTEN and autophagy as it is generally observed to be negligible in PTEN deficient cancer cells. Here, we have shown that such modifications of PTEN namely sumoylation and phosphorylation upregulates and downregulates autophagy respectively. Transfection of plasmid containing full length PTEN in PTEN-negative prostate cancer cell line PC3, induced autophagy on further starvation. When a sumoylation-deficient mutant of PTEN was transfected and cells were put under similar starvation, a decline in autophagy was observed. On the other hand, cells transfected with phosphorylation-deficient mutant of PTEN showed elevated expression of autophagy. Contrarily, transfection with phosphorylation-mimicking mutant caused reduced expression of autophagy. On further analysis, it was detected that PTEN's association with the plasma membrane was under positive and negative influence from its sumoylation and phosphorylation respectively. This association is integral as it is the foremost site for PTEN to oppose PI3K/AKT pathway and consequently upregulate autophagy. Thus, this study indicates that sumoylation and phosphorylation of PTEN can control autophagy via its cell membrane association.

Keywords:  Autophagic vacuoles; Cell membrane localisation; PI3K/AKT pathway; Post-translational modifications; mTOR

DOI:  https://doi.org/10.1016/j.yexcr.2023.113872
Med. 2023 Dec 08. pii: S2666-6340(23)00365-3. [Epub ahead of print]4(12): 857-859

Revolutionizing KRAS p.G12C therapy in metastatic colorectal cancer: The triumph of dual inhibition.

Alessandro Ottaiano, Mariachiara Santorsola.

The management of refractory metastatic colorectal cancer patients with the KRAS p.G12C mutation presents a significant unmet need, with limited success using standard therapies. The study by Fakih et al. highlights the potential of sotorasib and panitumumab combination therapy in this clinical context, paving the way for a promising personalized therapeutic approach.1.

DOI: https://doi.org/10.1016/j.medj.2023.11.005
Cell. 2023 Dec 07. pii: S0092-8674(23)01220-5. [Epub ahead of print]186(25): 5606-5619.e24

Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses.

María Ramos Zapatero, Alexander Tong, James W Opzoomer, Rhianna O'Sullivan, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Callum Nattress, Xiao Qin, Jeroen Claus, Daniel Hochhauser, Smita Krishnaswamy, Christopher J Tape.

  Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post-translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed "Trellis"-a highly scalable, tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity-shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy.

Keywords:  CAFs; PDOs; PTM signaling; Trellis; cancer associated fibroblasts; chemoresistance; mass cytometry; patient-derived organoids; plasticity; scRNA-seq; single-cell screening

DOI:  https://doi.org/10.1016/j.cell.2023.11.005
Nature. 2023 Dec;624(7991): 258-260

MYC protein helps cancer to take its vitamins.

Martina Wallace.



Keywords:  Cancer; Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-023-03764-2