bims-stacyt 2021-01-17 papers

Cancer Lett. 2021 Jan 11. pii: S0304-3835(20)30680-7. [Epub ahead of print]

Metabolic adaptation in hypoxia and cancer.

Felipe Paredes, Holly C Williams, Alejandra San Martin.

The ability of tumor cells to adapt to changes in oxygen tension is essential for tumor development. Low oxygen concentration influences cellular metabolism and, thus, affects proliferation, migration, and invasion. A focal point of the cell's adaptation to hypoxia is the transcription factor HIF1α (hypoxia-inducible factor 1 alpha), which affects the expression of specific gene networks involved in cellular energetics and metabolism. This review illustrates the mechanisms by which HIF1α-induced metabolic adaptation promotes angiogenesis, participates in the escape from immune recognition, and increases cancer cell antioxidant capacity. In addition to hypoxia, metabolic inhibition of 2-oxoglutarate-dependent dioxygenases regulates HIF1α stability and transcriptional activity. This phenomenon, known as pseudohypoxia, is frequently used by cancer cells to promote glycolytic metabolism to support biomass synthesis for cell growth and proliferation. In this review, we highlight the role of the most important metabolic intermediaries that are at the center of cancer's biology, and in particular, the participation of these metabolites in HIF1α retrograde signaling during the establishment of pseudohypoxia. Finally, we will discuss how these changes affect both the development of cancers and their resistance to treatment.

Keywords: Hypoxia; Metabolites; Pseudo-hypoxia; TCA

DOI: https://doi.org/10.1016/j.canlet.2020.12.020

J Cell Physiol. 2021 Jan 09.

Overexpression of GLUT3 promotes metastasis of triple-negative breast cancer by modulating the inflammatory tumor microenvironment.

Tai-Hua Tsai, Ching-Chieh Yang, Tai-Chih Kou, Chang-En Yang, Jia-Zih Dai, Chia-Ling Chen, Cheng-Wei Lin.

Triple-negative breast cancer (TNBC) exhibits a higher level of glycolytic capacity and are commonly associated with an inflammatory microenvironment, but the regulatory mechanism and metabolic crosstalk between the tumor and tumor microenvironment (TME) are largely unresolved. Here, we show that glucose transporter 3 (GLUT3) is particularly elevated in TNBC and associated with metastatic progression and poor prognosis in breast cancer patients. Expression of GLUT3 is crucial for promoting the epithelial-to-mesenchymal transition and enhancing invasiveness and distant metastasis of TNBC cells. Notably, GLUT3 is correlated with inflammatory gene expressions and is associated with M1 tumor-associated macrophages (TAMs), at least in part by C-X-C Motif Chemokine Ligand 8 (CXCL8). We found that expression of GLUT3 regulates CXCL8 production in TNBC cells. Secretion of CXCL8 participates in GLUT3-overexpressing TNBC cells-elicited activation of inflammatory TAMs, which further enhances GLUT3 expression and mobility of TNBC cells. Our findings demonstrate that aerobic glycolysis in TNBC not only promotes aggressiveness of tumor cells but also initiates a positive regulatory loop for enhancing tumor progression by modulating the inflammatory TME.

Keywords: glycolysis; inflammation; triple-negative breast cancer; tumor microenvironment; tumor-associated macrophage

DOI: https://doi.org/10.1002/jcp.30189

J Exp Clin Cancer Res. 2021 Jan 11. 40(1): 28

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons.

Muhlis Akman, Dimas Carolina Belisario, Iris Chiara Salaroglio, Joanna Kopecka, Massimo Donadelli, Enrico De Smaele, Chiara Riganti.

Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.

Keywords: Chemoresistance; Endoplasmic reticulum stress; Hypoxia; Hypoxia-inducible factor-1α; Unfolded protein response

DOI: https://doi.org/10.1186/s13046-020-01824-3

Proc Natl Acad Sci U S A. 2021 Jan 19. pii: e2011342118. [Epub ahead of print]118(3):

The harsh microenvironment in early breast cancer selects for a Warburg phenotype.

Mehdi Damaghi, Jeffrey West, Mark Robertson-Tessi, Liping Xu, Meghan C Ferrall-Fairbanks, Paul A Stewart, Erez Persi, Brooke L Fridley, Philipp M Altrock, Robert A Gatenby, Peter A Sims, Alexander R A Anderson, Robert J Gillies.

The harsh microenvironment of ductal carcinoma in situ (DCIS) exerts strong evolutionary selection pressures on cancer cells. We hypothesize that the poor metabolic conditions near the ductal center foment the emergence of a Warburg Effect (WE) phenotype, wherein cells rapidly ferment glucose to lactic acid, even in normoxia. To test this hypothesis, we subjected low-glycolytic breast cancer cells to different microenvironmental selection pressures using combinations of hypoxia, acidosis, low glucose, and starvation for many months and isolated single clones for metabolic and transcriptomic profiling. The two harshest conditions selected for constitutively expressed WE phenotypes. RNA sequencing analysis of WE clones identified the transcription factor KLF4 as potential inducer of the WE phenotype. In stained DCIS samples, KLF4 expression was enriched in the area with the harshest microenvironmental conditions. We simulated in vivo DCIS phenotypic evolution using a mathematical model calibrated from the in vitro results. The WE phenotype emerged in the poor metabolic conditions near the necrotic core. We propose that harsh microenvironments within DCIS select for a WE phenotype through constitutive transcriptional reprogramming, thus conferring a survival advantage and facilitating further growth and invasion.

Keywords: DCIS; Warburg Effect; adaptation; clonal selection; tumor evolution

DOI: https://doi.org/10.1073/pnas.2011342118

Cancers (Basel). 2021 Jan 12. pii: E261. [Epub ahead of print]13(2):

An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer.

Claire M Robinson, Aaron Talty, Susan E Logue, Katarzyna Mnich, Adrienne M Gorman, Afshin Samali.

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.

Keywords: activating transcription factor 6 (ATF6); endoplasmic reticulum (ER); inositol-requiring enzyme 1 (IRE1); protein kinase RNA-like ER kinase (PERK); unfolded protein response (UPR)

DOI: https://doi.org/10.3390/cancers13020261

Mol Cell Proteomics. 2019 May;pii: S1535-9476(20)31604-2. [Epub ahead of print]18(5): 936-953

Metabolic, Anti-apoptotic and Immune Evasion Strategies of Primary Human Myeloma Cells Indicate Adaptations to Hypoxia.

Lukas Janker, Rupert L Mayer, Andrea Bileck, Dominique Kreutz, Johanna C Mader, Kirsten Utpatel, Daniel Heudobler, Hermine Agis, Christopher Gerner, Astrid Slany.

Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry similar initial mutations as found in MM cells. Over the last years, increased importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to hypoxic conditions in the BM have been shown to contribute significantly to MM progression, independently from the genetic predispositions of the tumor cells. Searching for consequences of hypoxia-induced adaptations in primary human MM cells, CD138-positive plasma cells freshly isolated from BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling, which resulted in the identification of 6218 proteins. Results have been made fully accessible via ProteomeXchange with identifier PXD010600. Data previously obtained from normal primary B cells were included for comparative purposes. A principle component analysis revealed three clusters, differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing these three clusters pointed to the alteration of pathways indicating adaptations to hypoxic stress in MM cells on disease progression. Protein regulations indicating immune evasion strategies of MM cells were determined, supported by immunohistochemical staining, as well as transcription factors involved in MM development and progression. Protein regulatory networks related to metabolic adaptations of the cells became apparent. Results were strengthened by targeted analyses of a selected panel of metabolites in MM cells and MM-associated fibroblasts. Based on our data, new opportunities may arise for developing therapeutic strategies targeting myeloma disease progression.

Keywords: Cancer Biology*; Hypoxia; Immune evasion; Immunohistochemistry; Mass Spectrometry; Metabolic adaptations; Metabolomics; Multiple Myeloma; Primary human myeloma cells; Tandem Mass Spectrometry

DOI: https://doi.org/10.1074/mcp.RA119.001390