Biology subjects

Haemmerle, M.

Publications and source records attributed to Haemmerle, M..

4 recordsLinked to original sources

bioRxiv2024

FOXM1 regulates platelet-induced anoikis resistance in pancreatic cancer cells

Anoikis resistance is a prerequisite for circulating tumor cells (CTC) to survive in the blood stream. Platelets can interact with these CTCs and protect them from cytokine and immune cell-mediated cell death. Whether platelets can regulate anoikis resistance by controlling tumor cell intrinsic gene expression changes has not been studied in pancreatic cancer cells in detail before. Here, we identified FOXM1 as a differentially regulated gene between attached and detached cells whose expression was controlled by platelets. Manipulating FOXM1 expression using FOXM1 knockdown and overexpression or by inhibiting its function using a small molecular inhibitor highlighted the role of FOXM1 in controlling platelet-mediated anoikis resistance in pancreatic cancer cells. Hence, targeting FOXM1 might be a novel therapeutic strategy in pancreatic cancer patients, especially in those with thrombocytosis.

cancer biology↗

bioRxiv2024

Screening great ape museum specimens for DNA viruses

Natural history museum collections harbour a record of wild species from the past centuries, providing a unique opportunity to study animals as well as their infectious agents. Thousands of great ape specimens are kept in these collections, and could become an important resource for studying the evolution of DNA viruses. Their genetic material is likely to be preserved in dry museum specimens, as reported previously for monkeypox virus genomes from historical orangutan specimens. Here, we screened 209 great ape museum specimens for 99 different DNA viruses, using hybridization capture coupled with short-read high-throughput sequencing. We determined the presence of multiple viruses within this dataset from historical specimens and obtained several near-complete viral genomes. In particular, we report high-coverage (>18-fold) hepatitis B virus genomes from one gorilla and two chimpanzee individuals, which are phylogenetically placed within clades infecting the respective host species.

genomics↗

bioRxiv2024

A complete mitochondrial genome of a Roman-era Plasmodium falciparum

Malaria has historically been one of the leading infection-related causes of death in human populations. To this day, it continues to pose a significant public health threat in African countries, particularly among children. Humans are affected by five Plasmodium species, with Plasmodium falciparum being the most lethal. The study of pathogenic DNA from ancient human remains has been vital in understanding the origin, evolution, and virulence of human-infecting pathogens. However, there have been no complete pre-20th century mitochondrial DNA (mtDNA) or genomic sequences of Plasmodium falciparum reported to date. This gap in knowledge makes it difficult to understand the genetic dynamics of this pathogen in the past. The difficulty in identifying ancient malaria cases through bioarchaeology and the infrequent presence of Plasmodium DNA in ancient bones contribute to these limitations. Here, we present the first complete mtDNA genome of P. falciparum recovered from an archaeological skeleton (a 2nd century CE Roman individual from Italy). The study of the 43-fold mtDNA genome supports the hypothesis of an Indian origin for P. falciparum in Europe and provides evidence for the genetic continuity of this lineage over the past 2,000 years. Additionally, our research highlights that extensive sampling may be necessary for malaria screening to gain insights into the evolution of this vector-borne disease from archaeological samples.

genomics↗

bioRxiv2023

IGF2BP1 induces high-risk neuroblastoma and forms a druggable feedforward loop with MYCN promoting 17q oncogene expression

BackgroundNeuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment. MethodsCandidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models. ResultsWe reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho- adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1- driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also in vivo. ConclusionWe reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feed-forward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.

cancer biology↗