bims-stacyt 2022-02-27 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2022‒02‒27
ten papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis.
Oncometabolites-A Link between Cancer Cells and Tumor Microenvironment.
The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?
Rapamycin ameliorates chronic intermittent hypoxia and sleep deprivation-induced renal damage via the mammalian target of rapamycin (mTOR)/NOD-like receptor protein 3 (NLRP3) signaling pathway.
Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.
Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.
Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.
Camptothecin effectively treats obesity in mice through GDF15 induction.
Stromal Oncostatin M cytokine promotes breast cancer progression by reprogramming the tumour microenvironment.
Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in hepatocellular carcinoma.

Biology (Basel). 2022 Feb 21. pii: 339. [Epub ahead of print]11(2):

The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis.

Ola Habanjar, Mona Diab-Assaf, Florence Caldefie-Chezet, Laetitia Delort.

  Tumor metastasis is a major cause of death in cancer patients. It involves not only the intrinsic alterations within tumor cells, but also crosstalk between these cells and components of the tumor microenvironment (TME). Tumorigenesis is a complex and dynamic process, involving the following three main stages: initiation, progression, and metastasis. The transition between these stages depends on the changes within the extracellular matrix (ECM), in which tumor and stromal cells reside. This matrix, under the effect of growth factors, cytokines, and adipokines, can be morphologically altered, degraded, or reorganized. Many cancers evolve to form an immunosuppressive TME locally and create a pre-metastatic niche in other tissue sites. TME and pre-metastatic niches include myofibroblasts, immuno-inflammatory cells (macrophages), adipocytes, blood, and lymphatic vascular networks. Several studies have highlighted the adipocyte-macrophage interaction as a key driver of cancer progression and dissemination. The following two main classes of macrophages are distinguished: M1 (pro-inflammatory/anti-tumor) and M2 (anti-inflammatory/pro-tumor). These cells exhibit distinct microenvironment-dependent phenotypes that can promote or inhibit metastasis. On the other hand, obesity in cancer patients has been linked to a poor prognosis. In this regard, tumor-associated adipocytes modulate TME through the secretion of inflammatory mediators, which modulate and recruit tumor-associated macrophages (TAM). Hereby, this review describes the cellular and molecular mechanisms that link inflammation, obesity, and cancer. It provides a comprehensive overview of adipocytes and macrophages in the ECM as they control cancer initiation, progression, and invasion. In addition, it addresses the mechanisms of tumor anchoring and recruitment for M1, M2, and TAM macrophages, specifically highlighting their origin, classification, polarization, and regulatory networks, as well as their roles in the regulation of angiogenesis, invasion, metastasis, and immunosuppression, specifically highlighting the role of adipocytes in this process.

Keywords:  angiogenesis; cancer-associated adipocytes; cancer-associated fibroblasts; extracellular matrix; hypoxia; immune-inflammatory cells; macrophage polarization; metastasis; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/biology11020339
Biology (Basel). 2022 Feb 09. pii: 270. [Epub ahead of print]11(2):

Oncometabolites-A Link between Cancer Cells and Tumor Microenvironment.

Maksymilian Baryła, Aleksandra Semeniuk-Wojtaś, Letycja Róg, Leszek Kraj, Maciej Małyszko, Rafał Stec.

  The tumor microenvironment is the space between healthy tissues and cancer cells, created by the extracellular matrix, blood vessels, infiltrating cells such as immune cells, and cancer-associated fibroblasts. These components constantly interact and influence each other, enabling cancer cells to survive and develop in the host organism. Accumulated intermediate metabolites favoring dysregulation and compensatory responses in the cell, called oncometabolites, provide a method of communication between cells and might also play a role in cancer growth. Here, we describe the changes in metabolic pathways that lead to accumulation of intermediate metabolites: lactate, glutamate, fumarate, and succinate in the tumor and their impact on the tumor microenvironment. These oncometabolites are not only waste products, but also link all types of cells involved in tumor survival and progression. Oncometabolites play a particularly important role in neoangiogenesis and in the infiltration of immune cells in cancer. Oncometabolites are also associated with a disrupted DNA damage response and make the tumor microenvironment more favorable for cell migration. The knowledge summarized in this article will allow for a better understanding of associations between therapeutic targets and oncometabolites, as well as the direct effects of these particles on the formation of the tumor microenvironment. In the future, targeting oncometabolites could improve treatment standards or represent a novel method for fighting cancer.

Keywords:  fumarate; glutamate; lactate; oncometabolite; succinate

DOI:  https://doi.org/10.3390/biology11020270
Front Immunol. 2022 ;13 828875

The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?

Raefa Abou Khouzam, Rania Faouzi Zaarour, Klaudia Brodaczewska, Bilal Azakir, Goutham Hassan Venkatesh, Jerome Thiery, Stéphane Terry, Salem Chouaib.

  Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized conditions that act to dampen immune cell function. Through its impact on key cancer hallmarks and by creating a physical barrier conducive to tumor survival, hypoxia modulates tumor cell escape from the mounted immune response. The tumor cell-immune cell crosstalk in the context of a hypoxic TME tips the balance towards a cold and immunosuppressed microenvironment that is resistant to immune checkpoint inhibitors (ICI). Nonetheless, evidence is emerging that could make hypoxia an asset for improving response to ICI. Tackling the tumor immune contexture has taken on an in silico, digitalized approach with an increasing number of studies applying bioinformatics to deconvolute the cellular and non-cellular elements of the TME. Such approaches have additionally been combined with signature-based proxies of hypoxia to further dissect the turbulent hypoxia-immune relationship. In this review we will be highlighting the mechanisms by which hypoxia impacts immune cell functions and how that could translate to predicting response to immunotherapy in an era of machine learning and computational biology.

Keywords:  genetic instability; hypoxia; hypoxia signature; immune microenvironment; immunogenicity; tumor microenvironment; tumor plasticity

DOI:  https://doi.org/10.3389/fimmu.2022.828875
Bioengineered. 2022 Mar;13(3): 5537-5550

Rapamycin ameliorates chronic intermittent hypoxia and sleep deprivation-induced renal damage via the mammalian target of rapamycin (mTOR)/NOD-like receptor protein 3 (NLRP3) signaling pathway.

Wei Liu, Dong Zhao, Xiaofeng Wu, Fang Yue, Haizhen Yang, Ke Hu.

  Rapamycin inhibits the activation of NOD-like receptor protein 3 (NLRP3) by regulating the mammalian target of rapamycin (mTOR) to treat obstructive sleep apnea-related renal injury. Sleep deprivation (SD) and chronic intermittent hypoxia (CIH) mouse models were used to assess the effects of autophagy in vivo. Compared with the control, SD, and CIH groups, the SD+CIH group had lower body weight and higher levels of blood urea nitrogen (BUN), creatinine, and urinary albumin (U-Alb) (P < 0.05); renal injury and oxidative damage occurred in the SD+CIH group, the kidney cell nucleus ruptured, and morphological structure of the cells was unclear in the SD+CIH group. The SD+CIH group demonstrated increased apoptosis compared with the control, SD, and CIH groups using Western blot analysis. Compared to the control, SD, and CIH groups, the SD+CIH group showed a higher degree of microtubule-associated protein light chain 3\ staining. Compared to the SD+CIH group, BUN, creatinine, and U-Alb levels decreased, and apoptosis increased in the SD+CIH+rapamycin group, and the structure of the kidney after rapamycin treatment was well preserved. The mTOR expression was increased in the kidneys of the SD+CIH group. The NLRP3, Gasdermin D (GMDSD), interleukin (IL)-18, IL-1β, and cleaved-caspase-1 protein levels were higher in the SD+CIH group than the SD+CIH+rapamycin group, and the NLRP3, GMDSD, IL-18, IL-1β, and cleaved-caspase-1 mRNA levels were higher in the SD+CIH group than the SD+CIH+rapamycin group. Following rapamycin treatment, pyroptosis was suppressed. Rapamycin ameliorates renal damage by inhibiting the mTOR/NLRP3 signaling pathway.

Keywords:  NLRP3; Rapamycin; chronic intermittent hypoxia; mTOR; renal damage; sleep deprivation

DOI:  https://doi.org/10.1080/21655979.2022.2037872
FASEB J. 2022 03;36(3): e22211

Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.

Steffen H Raun, Jonas Roland Knudsen, Xiuqing Han, Thomas E Jensen, Lykke Sylow.

  Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3 H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.

Keywords:  AMPK; Akt; Lewis lung carcinoma; TBC1D4; cachexia; cancer; glucose metabolism; insulin resistance; mTORC1; muscle

DOI:  https://doi.org/10.1096/fj.202101759R
EMBO Rep. 2022 Feb 24. e53746

Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.

Elisabeth Wyart, Myriam Y Hsu, Roberta Sartori, Erica Mina, Valentina Rausch, Elisa S Pierobon, Mariarosa Mezzanotte, Camilla Pezzini, Laure B Bindels, Andrea Lauria, Fabio Penna, Emilio Hirsch, Miriam Martini, Massimiliano Mazzone, Antonella Roetto, Simonetta Geninatti Crich, Hans Prenen, Marco Sandri, Alessio Menga, Paolo E Porporato.

  Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.

Keywords:  cachexia; iron; metabolism; mitochondria; muscle

DOI:  https://doi.org/10.15252/embr.202153746
Gastroenterology. 2022 Feb 21. pii: S0016-5085(22)00154-8. [Epub ahead of print]

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.

Carolina J Garcia Garcia, Yanqing Huang, Natividad R Fuentes, Madeleine C Turner, Maria E Monberg, Daniel Lin, Nicholas D Nguyen, Tara N Fujimoto, Jun Zhao, Jaewon J Lee, Vincent Bernard, Meifang Yu, Abagail M Delahoussaye, Iancarlos Jimenez Sacarello, Emily G Caggiano, Jae L Phan, Amit Deorukhkar, Jessica M Molkentine, Dieter Saur, Anirban Maitra, Cullen M Taniguchi.

  BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown.METHODS: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2 expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade.
RESULTS: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models.
CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

Keywords:  cancer-associated fibroblasts; hypoxia; pancreatic ductal adenocarcinoma; tumor-associated macrophages

DOI:  https://doi.org/10.1053/j.gastro.2022.02.024
PLoS Biol. 2022 Feb;20(2): e3001517

Camptothecin effectively treats obesity in mice through GDF15 induction.

Jun Feng Lu, Meng Qing Zhu, Bao Cai Xie, Xiao Chen Shi, Huan Liu, Rui Xin Zhang, Bo Xia, Jiang Wei Wu.

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.

DOI: https://doi.org/10.1371/journal.pbio.3001517
J Clin Invest. 2022 Feb 22. pii: e148667. [Epub ahead of print]

Stromal Oncostatin M cytokine promotes breast cancer progression by reprogramming the tumour microenvironment.

Angela M Araujo, Andrea Abaurrea, Peio Azcoaga, Joanna I López-Velazco, Sara Manzano, Javier Rodriguez, Ricardo Rezola, Leire Egia-Mendikute, Fátima Valdés-Mora, Juana M Flores, Liam Jenkins, Laura Pulido, Iñaki Osorio-Querejeta, Patricia Fernández-Nogueira, Nicola Ferrari, Cristina Viera, Natalia Martin-Martin, Alexandar Tzankov, Serenella Eppenberger-Castori, Isabel Alvarez-Lopez, Ander Urruticoechea, Paloma Bragado, Nicholas Coleman, Asis Palazon, Arkaitz Carracedo, David Gallego-Ortega, Fernando Calvo, Clare M Isacke, Maria M Caffarel, Charles H Lawrie.

  The tumour microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumour progression. The contribution of stromal cells to the reprogramming of the TME is not well-understood. Here we provide solid evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stromal cells and the epithelial cancer cell compartment. Oncostatin M Receptor (OSMR) deletion in a multistage breast cancer model halted tumour progression. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype, elicited the secretion of VEGF and pro-inflammatory chemokines CXCL1 and CXCL16, leading to increased neutrophil and macrophage recruitment. Collectively, our data support that stromal OSM:OSMR axis reprograms the immune and non-immune microenvironment and plays a key role in breast cancer progression.

Keywords:  Breast cancer; Chemokines; Cytokines; Inflammation; Oncology

DOI:  https://doi.org/10.1172/JCI148667
Hepatology. 2022 Feb 20.

Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in hepatocellular carcinoma.

Sheena D/O Suthen, Chun Jye Lim, Phuong H D Nguyen, Charles-Antoine Dutertre, Hannah L H Lai, Martin Wasser, Camillus Chua, Tony K H Lim, Wei Qiang Leow, Tracy Jiezhen Loh, Wei Keat Wan, Yin Huei Pang, Gwyneth Soon, Peng Chung Cheow, Juinn Huar Kam, Shridhar Iyer, Alfred Kow, Wai Leong Tam, Timothy W H Shuen, Han Chong Toh, Yock Young Dan, Glenn K Bonney, Chung Yip Chan, Alexander Chung, Brian K P Goh, Weiwei Zhai, Florent Ginhoux, Pierce K H Chow, Salvatore Albani, Valerie Chew.

  BACKGROUND AND AIMS: Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the hypoxic TME of hepatocellular carcinoma (HCC) remains to be elucidated.APPROACH AND RESULTS: We analyzed the immune landscapes of hypoxia-low and -high tumor regions using cytometry by time-of-flight (CyTOF), immunohistochemistry and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including type-2 macrophages and HLA-DRlo type-2 conventional dendritic cell (HLA-DRlo cDC2), were found to be significantly enriched in hypoxia-high tumor regions. On the other hand, the abundance of active granzyme Bhi PD-1lo CD8 T cells in hypoxia-low tumor regions implied a relatively active immune landscape compared to hypoxia-high regions. The upregulation of cancer-associated genes in the tumor tissues and immunosuppressive genes in the tumor infiltrating leukocytes (TILs) supported a highly pro-tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 and CXCL5 were associated with recruitment of both Tregs and HLA-DRlo cDC2 to hypoxia-high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen-presenting HLA-DR on cDC2.
CONCLUSIONS: We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg-mediated immunosuppression through interaction with cDC2 subset in HCC that could be exploited for novel immunotherapies.

Keywords:  HLA-DR; Lymphoid-myeloid interaction; Metabolic changes; liver cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/hep.32419