Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

Kemp, Samantha B.; Steele, Nina G.; Carpenter, Eileen S.; Donahue, Katelyn L.; Bushnell, Grace G.; Morris, Aaron H.; Orbach, Sophia M.; Sirihorachai, Veerin R.; Nwosu, Zeribe C.; Espinoza, Carlos; Lima, Fatima; Brown, Kristee; Girgis, Alexander; Gunchick, Valerie; Zhang, Yaqing; Lyssiotis, Costas A.; Frankel, Timothy L.; Bednar, Filip; Rao, Arvind; Sahai, Vaibhav; Shea, Lonnie D.; Crawford, Howard C.; Magliano, Marina Pasca di

doi:10.26508/lsa.202000935

Cited by 69 publications

(48 citation statements)

References 54 publications

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“…Additionally, we observed downregulation of the complement genes C1qa, C1qb, C1qc and the transcription factor Trem2, which together define TAMs in several malignancies (45). Our group has also recently described a population of C1qa + C1qb + Trem2 + macrophages enriched in human and mouse pancreatic cancer both at the primary tumor and in liver metastases (46). These findings are consistent with TAM gene expression markers being activated in macrophages during the onset of neoplasia.…”

Section: Extrinsic Signaling From Kras* Transformed Cells Drives Myeloid Polarizationsupporting

confidence: 86%

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Velez-Delgado

Donahue

Brown

et al. 2021

Preprint

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Oncogenic KRAS is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. While the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single cell RNA sequencing, we have discovered that non-cell autonomous (i.e., extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, mediating the polarization and function of pro-tumorigenic myeloid cells while also preventing tissue repair. Our study provides fundamental new knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

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Section: Extrinsic Signaling From Kras* Transformed Cells Drives Myeloid Polarizationsupporting

confidence: 86%

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Velez-Delgado

Donahue

Brown

et al. 2021

Preprint

Self Cite

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“…There are still different types of cancer (e.g., pancreatic cancer) that have not been analyzed in the context of NUCB2 expression. Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a dismal 5-year survival rate of only 10%, making it one of the most aggressive cancers worldwide [ 79 ]. Recent studies succeeded in isolating different pancreatic cell types from mouse and human pancreas [ 80 , 81 ].…”

Section: Nucb2 In Cancer Proliferation Apoptosis Migration and Invasionmentioning

confidence: 99%

Nucleobindin-2/Nesfatin-1—A New Cancer Related Molecule?

Kmiecik

Dzięgiel

Podhorska‐Okołów

2021

IJMS

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Cancer is a heterogeneous disease, and even tumors with similar clinicopathological characteristics show different biology, behavior, and treatment responses. As a result, there is an urgent need to define new prognostic and predictive markers to make treatment options more personalized. According to the latest findings, nucleobindin-2/nesfatin-1 (NUCB2/NESF-1) is an important factor in cancer development and progression. Nucleobindin-2 is a precursor protein of nesfatin-1. As NUCB2 and nesfatin-1 are colocalized in each tissue, their expression is often analyzed together as NUCB2. The metabolic function of NUCB2/NESF-1 is related to food intake, glucose metabolism, and the regulation of immune, cardiovascular and endocrine systems. Recently, it has been demonstrated that high expression of NUCB2/NESF-1 is associated with poor outcomes and promotes cell proliferation, migration, and invasion in, e.g., breast, colon, prostate, endometrial, thyroid, bladder cancers, or glioblastoma. Interestingly, nesfatin-1 is also considered an inhibitor of the proliferation of human adrenocortical carcinoma and ovarian epithelial carcinoma cells. These conflicting results make NUCB2/NESF-1 an interesting target of study in the context of cancer progression. The present review is the first to describe NUCB2/NESF-1 as a new prognostic and predictive marker in cancers.

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“…Consistently, C1QA and C1QB were confirmed to be drivers of alternatively activated macrophage polarization in a LPS-induced inflammation model (47). Samantha et al (48) reported that macrophages express high levels of C1QA and C1QB in both primary tumor and metastases. C3AR1 as a receptor of the complement effector C3a, is important in mediating the downstream signal transduction of the complement activation.…”

Section: Discussionmentioning

confidence: 73%

“…Samantha et al. ( 48 ) reported that macrophages express high levels of C1QA and C1QB in both primary tumor and metastases. C3AR1 as a receptor of the complement effector C3a, is important in mediating the downstream signal transduction of the complement activation.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Prognostic Gene Signature Correlated With M2 Macrophage Infiltration in Esophageal Squamous Cell Carcinoma

et al. 2021

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BackgroundEsophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer and the seventh most prevalent cause of cancer-related death worldwide. Tumor microenvironment (TME) has been confirmed to play an crucial role in ESCC progression, prognosis, and the response to immunotherapy. There is a need for predictive biomarkers of TME-related processes to better prognosticate ESCC outcomes.AimTo identify a novel gene signature linked with the TME to predict the prognosis of ESCC.MethodsWe calculated the immune/stromal scores of 95 ESCC samples from The Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm, and identified differentially expressed genes (DEGs) between high and low immune/stromal score patients. The key prognostic genes were further analyzed by the intersection of protein–protein interaction (PPI) networks and univariate Cox regression analysis. Finally, a risk score model was constructed using multivariate Cox regression analysis. We evaluated the associations between the risk score model and immune infiltration via the CIBERSORT algorithm. Moreover, we validated the signature using the Gene Expression Omnibus (GEO) database. Within the ten gene signature, five rarely reported genes were further validated with quantitative real time polymerase chain reaction (qRT-PCR) using an ESCC tissue cDNA microarray.ResultsA total of 133 up-regulated genes were identified as DEGs. Ten prognostic genes were selected based on intersection analysis of univariate COX regression analysis and PPI, and consisted of C1QA, C1QB, C1QC, CD86, C3AR1, CSF1R, ITGB2, LCP2, SPI1, and TYROBP (HR>1, p<0.05). The expression of 9 of these genes in the tumor samples were significantly higher compared to matched adjacent normal tissue based on the GEO database (p<0.05). Next, we assessed the ability of the ten-gene signature to predict the overall survival of ESCC patients, and found that the high-risk group had significantly poorer outcomes compared to the low-risk group using univariate and multivariate analyses in the TCGA and GEO cohorts (HR=2.104, 95% confidence interval:1.343-3.295, p=0.001; HR=1.6915, 95% confidence interval:1.053-2.717, p=0.0297). Additionally, receiver operating characteristic (ROC) curve analysis demonstrated a relatively sensitive and specific profile for the signature (1-, 2-, 3-year AUC=0.672, 0.854, 0.81). To identify the basis for these differences in the TME, we performed correlation analyses and found a significant positive correlation with M1 and M2 macrophages and CD8+ T cells, as well as a strong correlation to M2 macrophage surface markers. A nomogram based on the risk score and select clinicopathologic characteristics was constructed to predict overall survival of ESCC patients. For validation, qRT-PCR of an ESCC patient cDNA microarray was performed, and demonstrated that C1QA, C3AR1, LCP2, SPI1, and TYROBP were up-regulated in tumor samples and predict poor prognosis.ConclusionThis study established and validated a novel 10-gene signature linked with M2 macrophages and poor prognosis in ESCC patients. Importantly, we identified C1QA, C3AR1, LCP2, SPI1, and TYROBP as novel M2 macrophage-correlated survival biomarkers. These findings may identify potential targets for therapy in ESCC patients.

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Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

Cited by 69 publications

References 54 publications

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Nucleobindin-2/Nesfatin-1—A New Cancer Related Molecule?

Development and Validation of a Prognostic Gene Signature Correlated With M2 Macrophage Infiltration in Esophageal Squamous Cell Carcinoma

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