Biology subjects

Klotz, L. V.

Publications and source records attributed to Klotz, L. V..

4 recordsLinked to original sources

bioRxiv2026

Loss of the Y chromosome drives epigenetic and transcriptomic plasticity in lung adenocarcinoma

Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX. Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo. These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.

cancer biology↗

bioRxiv2025

msBayesImpute: A Versatile Framework for Addressing Missing Values in Biomedical Mass Spectrometry Proteomics Data

Advancements in mass spectrometry (MS) technologies have significantly improved the ability to quantify proteins and analyse their modifications. However, MS-based proteomics datasets frequently encounter missing values due to a complex interplay of missing at random (MAR) and missing not at random (MNAR) mechanisms. If unaddressed, such missing data can result in information loss and biased outcomes in data pre-processing, such as normalisation, as well as subsequent analyses and interpretations. Few approaches effectively address both MAR and MNAR, and those that do often necessitate manual tuning of mixture percentages between them or rely on two-group experimental designs. To enhance the handling of missing values, we developed msBayesImpute, an innovative computational method that integrates Bayesian factorization with probabilistic dropout models. We evaluated msBayesImpute against several popular imputation methods using both simulated missing values and those generated through a dilution series experiment on samples from lung cancer patients. Our comprehensive benchmark demonstrated superior performance in reconstructing missing values, estimating normalization factors, and identifying differentially expressed proteins across varying levels of missingness. Notably, msBayesImpute does not require predefined experimental designs and is scalable to large-scale studies. This versatility positions msBayesImpute as an effective and robust tool for enhancing the utility of MS datasets in biological research.

bioinformatics↗

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↗

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↗