Biology subjects

Spella, M.

Publications and source records attributed to Spella, M..

4 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↗

bioRxiv2020

KRAS signalling in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes like BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here we show that a significant proportion of human MPM harbour point mutations and copy number alterations in the KRAS proto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS mutations likely play an important and underestimated role in MPM, which warrants further exploration.

physiology↗

bioRxiv2019

Dual airway and alveolar contributions to adult lung homeostasis and carcinogenesis

Lung adenocarcinoma (LUAD) and chronic lung diseases caused by smoking and environmental noxious agents are the deadliest diseases worldwide, sharing a partially charted pathobiology of dysfunctional alveolar repair. Here we sought to identify the respiratory epithelial dynamics and molecular signatures participating in adult lung maintenance and chemical carcinogenesis. We employed novel mouse models of respiratory epithelial marking and ablation, a battery of pulmonary toxins and carcinogens, experimental protocols of carcinogen-induced LUAD, tobacco carcinogen-induced LUAD cell lines, and human transcriptomic data and identified a prominent involvement of airway molecular programs in alveolar maintenance and carcinogen-induced LUAD. The airway-specific transcriptomic signature was redistributed to the alveoli after toxic and carcinogenic insults and resulted in marked contributions of airway-labeled cells to injury-recovered alveoli and LUAD. Airway cells maintained Kras mutations and therefore possibly contributed to lung cancer initiation, while LUAD were spatially linked to neighboring airways. Transcriptomic profiling of carcinogen-induced murine and human LUAD revealed enrichment in airway signatures, while ablation of airway cells distorted alveolar structure and function and protected mice from LUAD development. Collectively, these results indicate that airway cells and/or transcriptomic signatures are essential for alveolar maintenance and LUAD development.

cancer biology↗