Biology subjects

Lange, M. J.

Publications and source records attributed to Lange, M. J..

4 recordsLinked to original sources

bioRxiv2025

DUSP11 is an intracellular innate immune checkpoint in lung adenocarcinoma

The discovery of immune checkpoints and the rapid growth of immuno-oncology (IO) have sparked tremendous efforts to utilize the immune system to treat a wide range of cancer types/subtypes. While the major focus of IO over the past decades has been to manipulate the adaptive immune system, recent attention has been given to manipulating the innate immune system to treat cancer and/or to enhance adaptive responses. In this work we detail the intracellular protein, Dual Specificity Phosphatase 11 (DUSP11), as an innate immune checkpoint (iIC) in Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma (LUAD). Expression of this atypical phosphatase is correlated with patient survival for multiple cancer types, and we show here that its activity is important for the viability of lung cancer cells in vitro. Specifically, we demonstrate that DUSP11 knockdown in LUAD cells induces apoptosis and an innate immune response capable of activating other cells in vitro, and we provide evidence that these phenotypes are primarily mediated by the pattern recognition receptor, retinoic acid inducible gene I (RIG-I). Finally, we show that expression of DUSP11 is important for tumor engraftment and growth of human LUAD in mice. Overall, these data are the first to establish DUSP11 as an immunosuppressive, pro-neoplastic, and potentially targetable protein in LUAD. In addition, our data suggests that the anti-cancer mechanisms induced by diminishing the activity of DUSP11 are likely to be generalizable to other cancer types such as breast cancer, warranting future investigation and therapeutic development.

cancer biology↗

bioRxiv2020

Lipidated poly(amino acid) nanostructures as versatile therapeutic delivery vehicles

Poly(amino acid)s are a diverse and capable class of polymers with significant potential for utilization in a wide variety of drug delivery applications. A sub-class of these biomaterials known as lipidated poly(amino acid)s (LPAAs) are amphiphiles composed of both hydrophobic and hydrophilic domains yielding interesting physical properties. In this article, we describe our efforts in developing a novel class of lysine and valine containing LPAAs synthesized via hexadecylamine initiated N-carboxyanhydride ring-opening polymerization (NCA-ROP). These highly hydrophobic LPAAs were found capable of undergoing hydrophobically-driven self-assembly into small nanostructures as well as being forced into larger nanostructures using a novel dump-and-stir nanoprecipitation process. This process yielded fine control over resulting nanoparticle size and cargo entrapment. Furthermore, cell-targeting DNA aptamer modification of doxorubicin-loaded LPAA nanoparticles induced significant death of co-incubated Non-Hodgkin Lymphoma cells providing exciting evidence of the therapeutic potential of this novel biomaterials-based delivery device.

bioengineering↗

bioRxiv2018

Activation of innate immune responses by a CpG oligonucleotide sequence composed entirely of threose nucleic acid.

Recent advances in synthetic biology have led to the development of nucleic acid polymers with backbone structures distinct from those found in nature, termed xeno-nucleic acids (XNAs). Several unique properties of XNAs make them attractive as nucleic acid therapeutics, most notably their high resistance to serum nucleases and ability to form Watson-Crick base-pairing with DNA and RNA. The ability of XNAs to induce immune responses has not been investigated. Threose nucleic acid (TNA), a type of XNA, is recalcitrant to nuclease digestion and capable of undergoing Darwinian evolution to produce high affinity aptamers; thus, TNA is an attractive candidate for diverse applications, including nucleic acid therapeutics. Here, we evaluated a TNA oligonucleotide derived from a CpG oligonucleotide sequence known to activate TLR9-dependent immune signaling in B cell lines. We observed a slight induction of relevant mRNA signals, robust B cell line activation, and negligible effects on cellular proliferation.

synthetic biology↗

bioRxiv2018

Poly-Target Selection Identifies RNA Broad-Spectrum Inhibitors of HIV Reverse Transcriptases

Aptamer selections often yield distinct subpopulations, each with unique phenotypes that can be leveraged for specialized applications. RNA aptamers that bind HIV-1 reverse transcriptase (RT) exhibit potent RT inhibition and suppress viral replication when targeting the strain-specific RT that they were originally selected to bind, but some of these same aptamers fail against single-point mutant and phylogenetically-diverse RTs. We hypothesized that a subset of the total aptamer population in libraries pre-enriched against a single RT may exhibit broad-spectrum RT binding and inhibition, and we devised a multiplexed Poly-Target selection approach to elicit those phenotypes against a panel of diverse primate lentiviral RTs. High-throughput sequencing of starting, negative, and final libraries, followed by analysis of coenrichment and codepletion in parallel and duplicate selection trajectories, narrowed the list of candidate aptamers by orders of magnitude. Biochemical characterization of candidates identified a novel aptamer motif and several rare and unobserved variants of previously-known motifs that inhibited recombinant RTs from HIV-1, HIV-2 and SIV to varying degrees. These broad-spectrum aptamers also suppressed replication of viral constructs carrying phylogenetically-diverse RTs. The Poly-Target selection and coenrichment approach described herein is a generalizable strategy for identifying broad-spectrum behavior and cross-reactivity among related targets from combinatorial libraries.

molecular biology↗