Biology subjects

Kruspig, B.

Publications and source records attributed to Kruspig, B..

4 recordsLinked to original sources

bioRxiv2025

Increased mRNA translation delays lung adenocarcinoma initiation and exposes a therapeutic vulnerability to MEK inhibitors

Although protein synthesis inhibitors are being evaluated as anti-cancer agents, the dynamics of mRNA translation in early tumorigenesis are still poorly understood. We report that deletion of the mRNA-translation repressor, eIF4A2 in early KRAS-driven lung adenocarcinoma leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this overdriven protein synthesis landscape delays tumorigenesis and leads to appearance of clusters of non-proliferative, p21-positive KRAS-expressing cells in the lung. Administration of rapamycin to reduce mRNA translation suppresses senescence and restores tumorigenesis following eIF4A2 deletion. Importantly, some eIF4A2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2+/+ lesions, these may be eradicated by administration of a MEK inhibitor. Thus, dysregulated mRNA translation exposes a potential therapeutic vulnerability in KRAS-driven lung adenocarcinoma by forcing cancer cells to rely on MEK signalling. Statement of significanceThe requirement for anabolism in cancers has led to the search for inhibitors of mRNA translation as anti-cancer agents. However, we report that increased rates of mRNA translation promote a senescence-like phenotype in KRAS-driven lung cancer which delays tumorigenesis and renders the resulting tumours sensitive to MEK inhibition.

cancer biology↗

bioRxiv2023

γδ T cells impair airway macrophage differentiation in lung adenocarcinoma

Protecting mucosal barriers, {gamma}{delta} T cells hold promise for the development of new cancer immunotherapies. In mice, {gamma}{delta} T cells can largely be segregated into CD27+ and CD27- cells, and their functions are modulated by interactions with surrounding cells. However, which cells communicate directly with {gamma}{delta} T cells in lung adenocarcinoma remains unknown. To address this, we combined flow cytometry, confocal microscopy, and scRNA-seq, using an autochthonous genetically engineered mouse model and different {gamma}{delta} T cell-deficient settings. We found that {gamma}{delta} T cells were increased in tumour-bearing lungs, with an altered phenotype. CD27- and CD27+ {gamma}{delta} T cells differed in their localisation and interactions including their tropism for macrophages. Overall, we propose a model where CD27+ {gamma}{delta} T cells undermine the differentiation of tumour-associated macrophages into airway macrophages, fostering a negative outcome in lung adenocarcinoma. Determining its translatability to human health may offer new avenues for immunotherapeutic strategies. SummaryGuardians of pulmonary homeostasis, {gamma}{delta} T cells remain enigmatic regarding their role in lung adenocarcinoma. Raffo-Iraolagoitia et al. report that a subset of {gamma}{delta} T cells impairs the differentiation of tumour-associated macrophages into airway macrophages, relevant for the outcome of lung adenocarcinoma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/557344v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@e679f7org.highwire.dtl.DTLVardef@15152dforg.highwire.dtl.DTLVardef@17eaa5org.highwire.dtl.DTLVardef@2e0e47_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma

Immunotherapy is increasingly viewed as treatment of choice for lung cancer, however, clinical responses to immune checkpoint blockade remain highly unpredictable and are largely transient. A deeper mechanistic understanding of the dynamics of tumour:immune interactions is needed to drive rational development of improved treatment strategies. Progress is hampered by a paucity of autochthonous model systems in which to interrogate the 2-way interactions of immune responses to evolving tumours and vice-versa. Specifically, commonly used genetically engineered mouse models typically lack the genetic diversity needed to drive an adaptive immune response. APOBEC mutagenesis signatures are prominent in lung cancer and APOBEC activity is predicted to drive immune visibility through Cytidine deaminase activity, coupled with inaccurate DNA-repair responses. We therefore generated a CRE-inducible APOBEC3B allele, interbred with multiple oncogenic drivers of lung adenocarcinoma, and used the resulting mice to investigate the response to PD1 blockade at single cell resolution. SIGNIFICANCE Using our novel immune-visible model of KRas-driven autochthonous lung adenocarcinoma, we uncovered a surprising increase in tumour-cell expression of EGFR/ERBB ligands following treatment with -PD1 and present evidence that transient ERBB blockade can restore immune surveillance in KRas mutant LuAd and combine effectively with immune checkpoint blockade.

cancer biology↗

bioRxiv2018

The ERBB network facilitates KRAS-driven lung tumorigenesis

KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling, however recent data suggest that this independence may not be absolute. Here we show that initiation and progression of KRAS-driven lung tumors requires input from ERBB family RTKs: Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRasG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS mutant tumor cells in culture and progression to invasive disease in vivo. Importantly, brief pharmacological inhibition of the ERBB network significantly enhances the therapeutic benefit of MEK inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.\n\nOne Sentence SummaryG12 Mutant KRAS requires tonic ERBB network activity for initiation and maintenance of lung cancer

cancer biology↗