Biology subjects

Lindberg, M.

Publications and source records attributed to Lindberg, M..

7 recordsLinked to original sources

bioRxiv2026

Ciliogenesis associated kinase 1 accumulates in its inactive form during polycystic kidney disease progression

Ciliogenesis associated kinase 1 (CILK1) deficiency in human and mice results in kidney developmental defects including cystogenesis. However, the biology of CILK1 in autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, remains to be investigated. Here, we show that CILK1 is overexpressed in dedifferentiated cells of renal tissue from ADPKD human patients in comparison to normal control tissue samples. We demonstrate that CILK1 overexpression results in protein accumulation in a non-phosphorylated inactive form. Using mouse polycystic kidney disease models, we reveal that inactive CILK1 accumulation is progressive over the course of disease progression. We show that genetic inactivation of the Polycystic Kidney Disease 1 (PKD1) gene is sufficient to trigger CILK1 accumulation. Altogether, these findings demonstrate that CILK1 regulation is altered in ADPKD and it represents a hallmark of disease progression.

biochemistry↗

bioRxiv2025

Early initiation of small intestine neuroendocrine tumors

Small intestine neuroendocrine tumor (SI-NET) is normally diagnosed late in life and has several unusual properties, including low proliferation rate, low mutation burden, lack of driver mutations, and frequent multifocality in the form of polyclonal tumor clusters. This sets SI-NET aside from other adult cancers and raises questions about the timeline of initiation and progression. Here, we investigated the evolutionary history of multifocal and unifocal SI-NET using whole genome sequencing data, obtaining timing information on primary tumors, metastases and key genetic events. Despite the late onset, the results indicated that major genetic alterations and the establishment of advanced metastatic tumor cell clones can often be traced back to childhood or adolescence in SINET. This was validated by re-examination of archival CT/MR scans, allowing longitudinal tracking of individual tumors up to 12 years prior. Metastases were detected at a high degree of consistency in the historical imaging data and estimated growth rates suggested several additional decades of tumor expansion. Collectively, our data support that slow growth of advanced lesions over half a century or more may precede SI-NET diagnosis in late adulthood.

cancer biology↗

bioRxiv2021

Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in uveal melanoma

Targeted therapy and immunotherapy have revolutionized the treatment of metastatic skin melanoma but none of the treatments are approved for patients with metastatic uveal melanoma (UM). Here we hypothesized that the poor responses to immunotherapy of UM can be enhanced by epigenetic modulation using HDAC or BET inhibitors (BETi). Cultured uveal melanoma cells were treated with the HDAC inhibitor (HDACi) entinostat or BETi JQ1. Entinostat induced HLA expression and PD-L1, but JQ1 did not. A syngenic mouse model carrying B16-F10 melanoma cells were treated with PD-1 and CTLA-4 inhibitors, which was curative. Co-treatment with the bioavailable BETi iBET-726 impaired the immunotherapy effect. Monotherapy of a B16-F10 mouse model with anti-PD-1 resulted in a moderate therapeutic effect that could be enhanced by entinostat. Mice carrying PD-L1 knockout B16-F10 cells were also sensitive to entinostat. This suggests HDAC inhibition and immunotherapy could work in concert. Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic UM is warranted.

cancer biology↗

bioRxiv2020

Multifocal small intestine neuroendocrine tumors form by independent somatic evolution

BackgroundSmall intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several intestinal tumors centered around a regional lymph node metastasis. Although SI-NET patients often present with metastatic disease at the time of diagnosis, there is an unusual absence of somatic driver mutations explaining tumor initiation and metastatic spread. The evolutionary trajectories that underlie multifocal SI-NET lesions could provide insight into the underlying tumor biology, but this question remains unresolved. Here, we determined the complete genome sequences of 65 tumor and tissue samples from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within individual patients. Intra-individual comparisons of whole genome sequences revealed a lack of shared somatic single-nucleotide variants and copy number alterations among the sampled intestinal lesions, supporting that they were of independent clonal origin. Furthermore, each metastasis originated from a single intestinal tumor, and in three of the patients, two independent tumors had metastasized. We conclude that primary multifocal SI-NETs generally arise from clonally independent cells, suggesting a contribution from of a cancer-priming local factor.

genomics↗

bioRxiv2019

Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Mutational signatures can reveal properties of underlying mutational processes and are important when assessing signals of selection in cancer. Here we describe the sequence characteristics of mutations induced by ultraviolet (UV) light, a major mutagen in several human cancers, in terms of extended (longer than trinucleotide) patterns as well as variability of the signature across chromatin states. Promoter regions display a distinct UV signature with reduced TCG>TTG transitions, and genome-wide mapping of UVB-induced DNA photoproducts (pyrimidine dimers) showed that this may be explained by decreased damage formation at hypomethylated promoter CpG sites. Further, an extended signature model encompassing additional information from longer patterns improves modeling of UV mutation rate, which may enhance discrimination between drivers and passenger events. Our study presents a refined picture of the UV signature and underscores that the characteristics of a single mutational process may vary across the genome.

genomics↗

bioRxiv2018

Elevated pyrimidine dimer formation at distinct genomic bases underlie promoter mutation hotspots in UV-exposed cancers

Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations have also been suggested to be due to locally inhibited DNA repair or, alternatively, locally increased propensity for UV damage. Here, we provide evidence that base-specific elevations in the efficacy of UV lesion formation underlie these mutations. First, we find that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER), ruling out inhibited repair. Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit a strong base-specific increase in CPD formation frequency. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory regions, we conclude that the most recurrently mutated individual DNA bases arise instead due to locally favorable conditions for UV damage formation, thus explaining a key phenomenon in whole-genome cancer analyses.

cancer biology↗

bioRxiv2018

14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface

Pseudomonas are a common cause of hospital acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, a hydrophobic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3{beta}:ExoS and -ExoT complexes presented here reveal an extensive novel binding interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the hydrophobic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the hydrophobic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the hydrophobic C-terminal segment.\n\nShort summaryCrystal structures of Pseudomonas exotoxins-S and -T identify a novel hydrophobic interface with 14-3-3 proteins, and we show that 14-3-3 activates these toxins independent of their phosphopeptide groove binding C-termini, by preventing their aggregation.

biochemistry↗