bims-pimaco 2022-04-10 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2022–04–10
ten papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

KRASG12R-Independent Macropinocytosis in Pancreatic Cancer.
Editorial: The Treatment of RAS or BRAF Mutated Metastatic Colorectal Cancer: Challenges and Perspectives.
Targeting KRAS with reversible inhibitors.
Wnt, GSK3, and Macropinocytosis.
Targeting mTOR in the context of diet and whole-body metabolism.
KRAS Addiction Promotes Cancer Cell Adaptation in Harsh Microenvironment Through Macropinocytosis.
Roles for 3' Phosphoinositides in Macropinocytosis.
KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer.
Circling back to PTEN: Fumarate inhibits canonical tumor suppressor.
Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells.

Subcell Biochem. 2022 ;98 205-221

KRASG12R-Independent Macropinocytosis in Pancreatic Cancer.

G Aaron Hobbs, Channing J Der.

  Macropinocytosis is a critical route of nutrient acquisition in pancreatic cancer cells. Constitutive macropinocytosis is promoted by mutant KRAS, which activates the PI3Kα lipid kinase and RAC1, to drive membrane ruffling, macropinosome uptake and processing. However, our recent study on the KRASG12R mutant indicated the presence of a KRAS-independent mode of macropinocytosis in pancreatic cancer cell lines, thereby increasing the complexity of this process. We found that KRASG12R-mutant cell lines promote macropinocytosis independent of KRAS activity using PI3Kγ and RAC1, highlighting the convergence of regulation on RAC signaling. While macropinocytosis has been proposed to be a therapeutic target for the treatment of pancreatic cancer, our studies have underscored how little we understand about the activation and regulation of this metabolic process. Therefore, this review seeks to highlight the differences in macropinocytosis regulation in the two cellular subtypes while also highlighting the features that make the KRASG12R mutant atypical.

Keywords:  KRAS; Macropinocytosis; Metabolism; Mutant-specific signaling; PI3K; Pancreatic cancer

DOI:  https://doi.org/10.1007/978-3-030-94004-1_11
Front Oncol. 2022 ;12 852445

Editorial: The Treatment of RAS or BRAF Mutated Metastatic Colorectal Cancer: Challenges and Perspectives.

Alessandro Ottaiano, Massimiliano Berretta, Claudia Von Arx, Monica Capozzi, Michele Caraglia.



Keywords:  BRAF; KRAS; colorectal cancer; prognosis; therapy

DOI:  https://doi.org/10.3389/fonc.2022.852445
Nat Rev Drug Discov. 2022 Apr 06.

Targeting KRAS with reversible inhibitors.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-022-00062-w
Subcell Biochem. 2022 ;98 169-187

Wnt, GSK3, and Macropinocytosis.

Nydia Tejeda-Muñoz, Edward M De Robertis.

  Here we review the regulation of macropinocytosis by Wnt growth factor signaling. Canonical Wnt signaling is normally thought of as a regulator of nuclear β-catenin, but emerging results indicate that there is much more than β-catenin to the Wnt pathway. Macropinocytosis is transiently regulated by EGF-RTK-Ras-PI3K signaling. Recent studies show that Wnt signaling provides for sustained acquisition of nutrients by macropinocytosis. Endocytosis of Wnt-Lrp6-Fz receptor complexes triggers the sequestration of GSK3 and components of the cytosolic destruction complex such as Axin1 inside multivesicular bodies (MVBs) through the action of the ESCRT machinery. Wnt macropinocytosis can be induced both by the transcriptional loop of stabilized β-catenin, and by the inhibition of GSK3 even in the absence of new protein synthesis. The cell is poised for macropinocytosis, and all it requires for triggering of Pak1 and the actin machinery is the inhibition of GSK3. Striking lysosomal acidification, which requires macropinocytosis, is induced by GSK3 chemical inhibitors or Wnt protein. Wnt-induced macropinocytosis requires the ESCRT machinery that forms MVBs. In cancer cells, mutations in the tumor suppressors APC and Axin1 result in extensive macropinocytosis, which can be reversed by restoring wild-type protein. In basal cellular conditions, GSK3 functions to constitutively repress macropinocytosis.

Keywords:  Colorectal cancer; ESCRT; Endocytosis; GSK3; Hepatocellular carcinoma; Lysosome regulation; Macropinocytosis; Multivesicular bodies; Wnt-STOP

DOI:  https://doi.org/10.1007/978-3-030-94004-1_9
Endocrinology. 2022 Apr 02. pii: bqac041. [Epub ahead of print]

Targeting mTOR in the context of diet and whole-body metabolism.

Nikos Koundouros, John Blenis.

  The mechanistic target of rapamycin (mTOR) signaling pathway is the central regulator of cell growth and proliferation by integrating growth factor and nutrient availability. Under healthy physiological conditions, this process is tightly coordinated and essential to maintain whole-body homeostasis. Not surprisingly, dysregulated mTOR signaling underpins several diseases with increasing incidence worldwide, including obesity, diabetes and cancer. Consequently, there is significant clinical interest in developing therapeutic strategies that effectively target this pathway. The transition of mTOR inhibitors from the bench to bedside, however, has largely been marked with challenges and shortcomings, such as the development of therapy resistance and adverse side effects in patients. In this review, we discuss the current status of first, second and third generation mTOR inhibitors as a cancer therapy in both pre-clinical and clinical settings, with a particular emphasis on the mechanisms of drug resistance. We focus especially on the emerging role of diet as an important environmental determinant of therapy response, and posit a conceptual framework that links nutrient availability and whole-body metabolic states such as obesity with many of the previously defined processes that drive resistance to mTOR-targeted therapies. Given the role of mTOR as a central integrator of cell metabolism and function, we propose that modulating nutrient inputs through dietary interventions may influence the signaling dynamics of this pathway and compensatory nodes. In doing so, new opportunities for exploiting diet/drug synergies are highlighted that may unlock the therapeutic potential of mTOR inhibitors as a cancer treatment.

Keywords:  diet; drug resistance; mTOR; metabolism

DOI:  https://doi.org/10.1210/endocr/bqac041
Subcell Biochem. 2022 ;98 189-204

KRAS Addiction Promotes Cancer Cell Adaptation in Harsh Microenvironment Through Macropinocytosis.

Laetitia Seguin.

  KRAS is the most frequently mutated oncogene in cancer and despite intensive studies, attempts to develop effective therapies targeting KRAS or its downstream signaling have failed mostly due to the complexity of KRAS activation and function in cancer initiation and progression. Over the years, KRAS has been involved in several biological processes including cell survival, proliferation, and metabolism by promoting not only a favorable tumor environment but also a cell-microenvironment dialog to allow cancer cells to adapt to tumor microenvironment scarcity. One of the mechanisms involved in this adaption is KRAS-mediated macropinocytosis. Macropinocytosis is an evolutionarily conserved, large-scale, and nonselective form of endocytosis involving actin-driven cell membrane remodeling to engulf large amounts of extracellular fluids and proteins from the local environment. While macropinocytosis process has been known for decades, recent gain interest due to its regulation of KRAS-driven tumor growth in adverse microenvironments. By promoting extracellular protein and other macromolecules internalization, macropinocytosis provides a survival mechanism under nutrient scarce conditions and the potential for unrestricted tumor growth. Thus, a better understanding of macropinocytotic process is needed to develop alternative therapeutic strategies.

Keywords:  Integrin; KRAS addiction; Macropinocytosis; Microenvironment sensing

DOI:  https://doi.org/10.1007/978-3-030-94004-1_10
Subcell Biochem. 2022 ;98 119-141

Roles for 3' Phosphoinositides in Macropinocytosis.

Joel A Swanson, Nobukazu Araki.

  The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions between those stages. Each stage in the process is regulated by variously phosphorylated derivatives of phosphatidylinositol (PtdIns) which reside in the cytoplasmic face of the membrane lipid bilayer. PtdIns derivatives phosphorylated at the 3' position of the inositol moiety, called 3' phosphoinositides (3'PIs), regulate different stages of the sequence. 3'PIs are synthesized by numerous phosphoinositide 3'-kinases (PI3K) and other lipid kinases and phosphatases, which are themselves regulated by small GTPases of the Ras superfamily. The combined actions of these enzymes localize four principal species of 3'PI to distinct domains of the plasma membrane or to discrete organelles, with distinct biochemical activities confined to those domains. Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) and phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2) regulate the early stages of macropinosome formation, which include cell surface ruffling and constrictions of circular ruffles which close into macropinosomes. Phosphatidylinositol 3-phosphate (PtdIns3P) regulates macropinosome fusion with other macropinosomes and early endocytic organelles. Phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P2) mediates macropinosome maturation and shrinkage, through loss of ions and water, and subsequent traffic to lysosomes. The different characteristic rates of macropinocytosis in different cell types indicate levels of regulation which may be governed by the cell's capacity to generate 3'PIs.

Keywords:  Macrophage; Macropinosome closure; Phosphatidylinositol 3-kinase; Ruffling

DOI:  https://doi.org/10.1007/978-3-030-94004-1_7
Mol Cancer Res. 2022 Apr 08. pii: molcanres.MCR-21-0994-A.2021. [Epub ahead of print]

KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer.

Seo-Hyun Choi, Jin K Kim, Chin-Tung Chen, Chao Wu, Michael R Marco, Francisco M Barriga, Kevin O'Rourke, Raphael Pelossof, Xuan Qu, Qing Chang, Elisa de Stanchina, Jinru Shia, J Joshua Smith, Francisco Sanchez-Vega, Julio Garcia-Aguilar.

KRAS mutation in colorectal cancer (CRC) is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS mutant CRC upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with integrin β4 knock-out KRAS mutant CRC cells compared to the mice injected with integrin β4 wild-type KRAS mutant CRC cells, while no difference was observed in liver metastases. Inhibiting integrin α6β4 in KRAS mutant CRC could be a potential therapeutic target to diminish the KRAS invasive phenotype and associated pulmonary metastasis rate. Implications: Knocking-out Integrin β4 (ITGB4), which is overexpressed in KRAS mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0994
Mol Cell. 2022 Apr 07. pii: S1097-2765(22)00222-2. [Epub ahead of print]82(7): 1244-1245

Circling back to PTEN: Fumarate inhibits canonical tumor suppressor.

Sally E Claridge, Benjamin D Hopkins.

Ge et al. (2022) describes an inhibitory, post-translational modification of PTEN at C211 by fumarate, which offers new insight into the integration of PI3K signaling and metabolism via a potential feedforward regulatory mechanism involving a PI3K-glucose-fumarate-PTEN axis.

DOI: https://doi.org/10.1016/j.molcel.2022.03.013
Nat Commun. 2022 Apr 05. 13(1): 1827

Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells.

Kathleen Shah, Muralidhara Rao Maradana, M Joaquina Delàs, Amina Metidji, Frederike Graelmann, Miriam Llorian, Probir Chakravarty, Ying Li, Mauro Tolaini, Michael Shapiro, Gavin Kelly, Chris Cheshire, Deendyal Bhurta, Sandip B Bharate, Brigitta Stockinger.

The aryl hydrocarbon receptor (AHR) is an environmental sensor that integrates microbial and dietary cues to influence physiological processes within the intestinal microenvironment, protecting against colitis and colitis-associated colorectal cancer development. Rapid tissue regeneration upon injury is important for the reinstatement of barrier integrity and its dysregulation promotes malignant transformation. Here we show that AHR is important for the termination of the regenerative response and the reacquisition of mature epithelial cell identity post injury in vivo and in organoid cultures in vitro. Using an integrative multi-omics approach in colon organoids, we show that AHR is required for timely termination of the regenerative response through direct regulation of transcription factors involved in epithelial cell differentiation as well as restriction of chromatin accessibility to regeneration-associated Yap/Tead transcriptional targets. Safeguarding a regulated regenerative response places AHR at a pivotal position in the delicate balance between controlled regeneration and malignant transformation.

DOI: https://doi.org/10.1038/s41467-022-29098-7