Biology subjects

de Bruijn, R.

Publications and source records attributed to de Bruijn, R..

6 recordsLinked to original sources

bioRxiv2022

CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer

Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice we determined that CAFs in both invasive lobular breast cancer and triple negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo tracing and in vitro studies revealed the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. In vitro functional assays showed that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data show that CD26+ and CD26- NFs transform into distinct CAF subpopulations in breast cancer.

cancer biology↗

bioRxiv2022

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR-defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi) but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combined molecular profiling with functional analysis of the HR status of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent functional restoration of BRCA1/2. We observed restoration of HR in 64% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we found that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by the loss of PARG. Our combined multi-omics analysis catalogued additional genes and pathways potentially involved in modulating PARPi response.

cancer biology↗

bioRxiv2022

A nucleation-and-growth model for the packaging of genome in linear virus-like particles: impact of multiple packaging signals

Inspired by recent experiments on the spontaneous assembly of virus-like particles from a solution containing a synthetic coat protein and double-stranded DNA, (1) we put forward a kinetic model that has as main ingredients a stochastic nucleation and a deterministic growth process. The efficiency and rate of the packaging of the DNA turn out to strongly increase by introducing proteins onto the DNA template that are modified using CRISPR-Cas techniques to bind specifically at predesignated locations, mimicking assembly signals in viruses. Our model shows that treating these proteins as nucleation-inducing diffusion barriers is sufficient to explain experimentally observed increase in encapsulation efficiency, but only if the nucleation rate is sufficiently high. We find an optimum in the encapsulation kinetics for conditions where the number of packaging signals is equal to the number of nucleation events that can occur during time required to fully encapsulate the DNA template, presuming that the nucleation events can only take place adjacent to a packaging signal. Our theory is in satisfactory agreement with the available experimental data. SIGNIFICANCEThe rate and efficiency of the encapsulation of double-stranded DNA by synthetic coat proteins was recently found to be strongly enhanced by the presence of specifically positioned protein molecules on the DNA that mimic so-called packaging signals. We present a kinetic theory based on the initial stochastic nucleation and subsequent deterministic elongation of the protein coat with the aim to explain these findings. We find that equidistantly placed nucleation sites that also act as diffusion barriers on the DNA have profound and non-trivial effects, and they can either slow down or speed up encapsulation, depending on how fast nucleation is on the time scale of the elongation process. Our findings may contribute to the rational design of linear virus-like particles.

biophysics↗

bioRxiv2021

MYC promotes immune-suppression in TNBC via inhibition of IFN signaling

Immune checkpoint inhibitor (ICI) treatment has thus far shown limited efficacy in triple-negative breast cancer (TNBC) patients, presumably due to sparse or unresponsive tumor-infiltrating lymphocytes. We reveal a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of BRCA1-proficient and -deficient TNBC, MYC overexpression dramatically decreased lymphocyte infiltration in tumors, along with immune signature loss. Likewise, MYC overexpression suppressed inflammatory signaling induced by BRCA1/2 inactivation in human TNBC cell lines. Moreover, MYC overexpression prevented the recruitment and activation of lymphocytes in co-cultures with human and mouse TNBC models. Chromatin immunoprecipitation (ChIP)-sequencing revealed that MYC directly binds promoters of multiple interferon-signaling genes, which were downregulated upon MYC expression. Finally, MYC overexpression suppressed induction of interferon signaling and tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist. Together, our data reveal that MYC suppresses innate immunity and facilitates immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs. Statement of SignificanceMYC suppresses recruitment and activation of immune cells in TNBC by repressing the transcription of interferon genes. These findings provide a mechanistic rationale for the association of high MYC expression levels with immune exclusion in human TNBCs, which might underlie the relatively poor response of many TNBCs to ICI.

cancer biology↗

bioRxiv2020

Brain transcriptomic changes in Japanese quail reveal a role for neurotensin in avian parental care

For many species, parental care critically affects offspring survival. But what drives animals to display parental behaviours towards young? In mammals, pregnancy-induced physiological transformations seem key in preparing the neural circuits that lead towards attraction (and reduced-aggression) to young. Beyond mammalian maternal behaviour, knowledge of the neural mechanisms that underlie parental care is severely lacking. We took advantage of a domesticated bird species, the Japanese quail, for which parental behaviour towards chicks can be induced through a sensitization procedure, a process that is not effective in all animals. We used the variation in parental responses to study neural transcriptomic changes associated with the sensitization procedure itself and with the outcome of the procedure (i.e., presence of parental behaviours). Out of the brain regions studied, we found that most differences in gene expression were located in the hypothalamus. Two genes identified are of particular interest, as no role in avian parental care was known for those genes. One is neurotensin, previously only demonstrated to be causally associated with maternal care in mammals. The other one is urocortin 3, causally demonstrated to affect young-directed neglect and aggression in mammals. Our work opens new avenues of research into understanding the neural basis of parental care in non-placental species.

animal behavior and cognition↗

bioRxiv2019

Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multi-region samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

cancer biology↗