bims-tumime 2023-09-10 papers

Issue of 2023–09–10
eight papers selected by
Alex Muir, University of Chicago

Front Oncol. 2023 ;13 1264439

Editorial: The tumor microenvironment and malignant properties in primary liver cancer.

Keywords: hepatocellular carcinoma; immunotherapy; liver cancer; prognosis; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2023.1264439

Sci Adv. 2023 Sep 08. 9(36): eadh2023

Loss of attachment promotes proline accumulation and excretion in cancer cells.

Steven E Pilley, Marc Hennequart, Anke Vandekeere, Julianna Blagih, Nathalie M Legrave, Sarah-Maria Fendt, Karen H Vousden, Christiaan F Labuschagne.

Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.

DOI: https://doi.org/10.1126/sciadv.adh2023

Am J Physiol Cell Physiol. 2023 Sep 04.

Intratumoral metabolic heterogeneity of colorectal cancer.

Yoshinobu Hirose, Kohei Taniguchi.

Although the metabolic phenotype within tumors is known to differ significantly from that of the surrounding normal tissue, the importance of this heterogeneity is just becoming widely recognized. Colorectal cancer (CRC) is often classified as the Warburg phenotype, a metabolic type in which the glycolytic system is predominant over oxidative phosphorylation (OXPHOS) in mitochondria for energy production. However, this dichotomy (glycolysis vs OXPHOS) may be too simplistic and not accurately represent the metabolic characteristics of CRC. Therefore, in this review, we decompose metabolic phenomena into factors based on their source/origin and reclassify them into two categories: extrinsic and intrinsic. In the CRC context, extrinsic factors include those based on the environment, such as hypoxia, nutrient deprivation, and the tumor microenvironment, whereas intrinsic factors include those based on subpopulations, such as pathological subtypes and cancer stem cells. These factors form multiple layers inside and outside the tumor, affecting them additively, dominantly, or mutually exclusively. Consequently, the metabolic phenotype is a heterogeneous and fluid phenomenon reflecting the spatial distribution and temporal continuity of these factors. This allowed us to redefine the characteristics of specific metabolism-related factors in CRC and summarize and update our accumulated knowledge on their heterogeneity. Furthermore, we positioned tumor budding in CRC as an intrinsic factor and a novel form of metabolic heterogeneity, and predicted its metabolic dynamics, noting its similarity to circulating tumor cells and epithelial-mesenchymal transition. Finally, the possibilities and limitations of using human tumor tissue as research material to investigate and assess metabolic heterogeneity are discussed.

Keywords: colorectal cancer; extrinsic factor; intrinsic factor; metabolic heterogeneity; multilayered model

DOI: https://doi.org/10.1152/ajpcell.00139.2021

Cells. 2023 Aug 22. pii: 2123. [Epub ahead of print]12(17):

The Influence of Adipocyte Secretome on Selected Metabolic Fingerprints of Breast Cancer Cell Lines Representing the Four Major Breast Cancer Subtypes.

Carla Luís, Bárbara Guerra-Carvalho, Patrícia C Braga, Carla Guedes, Emília Patrício, Marco G Alves, Ruben Fernandes, Raquel Soares.

Molecular subtype (MS) is one of the most used classifications of breast cancer (BC). Four MSs are widely accepted according to receptor expression of estrogen, progesterone, and HER2. The impact of adipose tissue on BC MS metabolic impairment is still unclear. The present work aims to elucidate the metabolic alterations in breast cancer cell lines representing different MSs subjected to adipocyte associated factors. Preadipocytes isolated from human subcutaneous adipose tissue were differentiated into mature adipocytes. MS representative cell lines were exposed to mature adipocyte secretome. Extracellular medium was collected for metabolomics and RNA was extracted to evaluate enzymatic expression by RT-PCR. Adipocyte secretome exposure resulted in a decrease in the Warburg effect rate and an increase in cholesterol release. HER2+ cell lines (BT-474 and SK-BR-3) exhibited a similar metabolic pattern, in contrast to luminal A (MCF-7) and triple negative (TN) (MDA-MB-231), both presenting identical metabolisms. Anaplerosis was found in luminal A and TN representative cells, whereas cataplerotic reactions were likely to occur in HER2+ cell lines. Our results indicate that adipocyte secretome affects the central metabolism distinctly in each BC MS representative cell line.

Keywords: Warburg effect; breast cancer; cancer cell metabolism; cell culture; molecular subtype; obesity

DOI: https://doi.org/10.3390/cells12172123

Front Med (Lausanne). 2023 ;10 1268976

Editorial: Tumor adaptation to cellular stresses: mechanisms, biomarkers and therapeutic opportunities.

Michela Cortesi, Giacomo Rossino, Anindita Chakrabarty, Daniela Rossi.

Keywords: ER stress; ROS; hypoxia; metabolic stress; mitochondrial stress; oxidative stress; tumor adaptation

DOI: https://doi.org/10.3389/fmed.2023.1268976

Cancer Metab. 2023 Sep 07. 11(1): 14

Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo.

Piotr Dzien, Agata Mackintosh, Gaurav Malviya, Emma Johnson, Dmitry Soloviev, Gavin Brown, Alejandro Huerta Uribe, Colin Nixon, Scott K Lyons, Oliver Maddocks, Karen Blyth, David Y Lewis.

BACKGROUND: Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment.
METHODS: We modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo.
RESULTS: NIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium-potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (- 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (- 16.6%) in A549 cells in vitro. PET signal was significantly decreased (- 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable.
CONCLUSIONS: NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

Keywords: 2-DG; Energy charge; IACS-010759; Metabolic sensor; Oligomycin A; Positron emission tomography; Reporter genes

DOI: https://doi.org/10.1186/s40170-023-00314-2

Int J Mol Sci. 2023 Aug 26. pii: 13260. [Epub ahead of print]24(17):

GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells.

Lorent Loxha, Nurul Khalida Ibrahim, Anna Sophie Stasche, Büsra Cinar, Tim Dolgner, Julia Niessen, Sabine Schreek, Beate Fehlhaber, Michael Forster, Martin Stanulla, Laura Hinze.

Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.

Keywords: GSK3α; Wnt/STOP; acute leukemia; amino acid starvation; asparaginase; cancer; colorectal cancer; gene regulation; metabolism; ribosomal proteins

DOI: https://doi.org/10.3390/ijms241713260

bioRxiv. 2023 Aug 22. pii: 2023.08.22.554238. [Epub ahead of print]

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.

Veani Fernando, Xunzhen Zheng, Vandana Sharma, Saori Furuta.

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2- TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH 4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH 4 precursor, elevates the expression of M1- TAM markers within HER2+ tumors. Here, we show that SEP restores BH 4 levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

DOI: https://doi.org/10.1101/2023.08.22.554238