Biology subjects

Ntaliarda, G.

Publications and source records attributed to Ntaliarda, G..

3 recordsLinked to original sources

bioRxiv2021

Immune-evasion of KRAS-mutant lung adenocarcinoma mediated by cAMP response element-binding protein

cAMP response element-binding protein (CREB) mediates proliferative and inflammatory gene transcription in neurodegeneration and cancer, but its role in malignant immune-evasion of lung adenocarcinoma (LUAD) is unknown. We show that human LUAD of smokers are frequently altered along the CREB pathway and we employ mouse models to discover that KRAS-mutant LUAD co- opt CREB to evade immune rejection by tumoricidal neutrophils. For this, KRAS- driven CREB activation suppresses CXC-chemokine expression and prevents recruitment of CXCR1+ neutrophils. CREB1 is shown to be pro-tumorigenic in five different LUAD models, a function that is dependent on host CXCR1. Pharmacologic CREB blockade prevents tumor growth and restores neutrophil recruitment only when initiated before immune-evasion of KRAS-mutant LUAD. CREB and CXCR1 expression in human LUAD are compartmentalized to tumor and stromal cells, respectively, while CREB-regulated genes and neutrophils impact survival. In summary, CREB-mediated immune evasion of KRAS-mutant LUAD relies on signaling to neutrophil CXCR1 and is actionable.

cancer biology↗

bioRxiv2021

Tumor-secreted versican co-opts myeloid IKKβ during metastasis

The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-{kappa}B reporter mice and macrophages to discover that metastatic tumors trigger NF-{kappa}B activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-{kappa}B in tumor-associated macrophages via inhibitor of NF-{kappa}B kinase (IKK) {beta}, resulting in release of interleukin (IL)-1{beta} into the tumor microenvironment. Versican silencing in cancer cells or conditional IKK{beta} deletion in macrophages prevents myeloid NF-{kappa}B activation and metastasis. Versican is overexpressed and/or mutated in human cancers and metastatic effusions with KRAS mutations, predicts poor survival, can aid in the development of diagnostic platforms for pleural metastasis, and is druggable via toll-like receptor (TLR) 1/2 inhibition. The data indicate a cardinal role for tumor-derived versican in establishing cross-talk with macrophage IKK{beta} during metastasis and may foster the development of new therapies and diagnostic tools.

cancer biology↗

bioRxiv2019

An in vivo inflammatory loop potentiates KRAS blockade

KRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-{delta}), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1{beta} signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1{beta} blockade might be specific for KRAS-mutant cancers.

cancer biology↗