Biology subjects

Klink, B.

Publications and source records attributed to Klink, B..

3 recordsLinked to original sources

bioRxiv2018

A stochastic model of metastatic bottleneck predicts patient outcome and therapy response

Metastases are responsible for 90% of cancer-related deaths. Initiation of metastases, where newly seeded tumor cells expand into colonies, presents a tremendous bottleneck to metastasis formation. Despite its clinical importance, our understanding of this process is very limited. Here, we propose a simple stochastic model assuming that the initiating metastatic cells proliferate faster when surrounded by more of their kind. The model quantifies the severity of metastatic bottleneck as the probability that the seeded colony survives. Based on this model, we derive how metastasis occurrence depends on primary tumor size and affects patient outcome. Our predictions agree with epidemiological data for thirteen cancer types. The model predicts that impact of treatment decisions depends both on the primary tumor size and on the severity of the metastatic bottleneck, and that medical interventions that tighten the bottleneck would be much more efficient than therapies that decrease overall tumor burden, such as chemotherapy.

cancer biology↗

bioRxiv2018

Patterns of tumor progression predict small and tissue-specific tumor-originating niches

Cancer development is a multistep process in which cells increase in malignancy through progressive alterations. The early phase of this process is hardly observable which aggravates an understanding of later tumor development. We shed light on this initial phase with a cell-based stochastic model calibrated with epidemiological data from the tissue scale. Our model allows to estimate the number of tumor cells needed for tumor formation in human tissues based on data on the diagnosed ratios of benign and malignant tumors. We find that the minimal number of cells needed for tumor formation is surprisingly small and largely depends on the tissue type. Our results point towards the existence of tumor-originating niches in which the fate of tumor development is early decided. Our estimate for the human colon agrees well with the size of the stem cell niche in colonic crypts. Our estimates might help to identify the tumor-originating cell type, e.g. our analysis suggests for glioblastoma that the tumors originate from a cell type competing in a range of 300 - 1900 cells.\n\nSummaryWe estimate the number of tumor cells needed for tumor formation in human tissues and propose the existence of small and tissue-specific tumor-originating niches which might help to find tumor-originating cell types, in particular in glioblastoma.

cancer biology↗

bioRxiv2018

Thrombocytopenia Microcephaly Syndrome - a novel phenotype associated with ACTB mutations

Introductory paragraphUntil recently missense germ-line mutations in ACTB, encoding the ubiquitously expressed {beta}-cytoplasmic actin (CYA), were exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), a complex developmental disorder1,2. Here, we report six patients with previously undescribed heterozygous variants clustered in the 3-coding region of ACTB. These patients present with clinical features different from BWCFF, including thrombocytopenia, microcephaly, and mild developmental disability. Patient derived cells are morphologically and functionally distinct from controls. Assessment of cytoskeletal constituents identified a discrete filament population altered in these cells, which comprises force generating and transmitting actin binding proteins (ABP) known to be associated with thrombocytopenia3-8. In silico modelling and molecular dynamics (MD)-simulations support altered interactions between these ABP and mutant {beta}-CYA. Our results describe a new clinical syndrome associated with ACTB mutations with a distinct genotype-phenotype correlation, identify a cytoskeletal protein interaction network crucial for thrombopoiesis, and provide support for the hypomorphic nature of these actinopathy mutations.

genetics↗