Biology subjects

Chan, B. C.

Publications and source records attributed to Chan, B. C..

3 recordsLinked to original sources

bioRxiv2025

Drug tolerant persisters and immunotherapy persister cells exhibit cross-resistance and share common survival mechanisms

Persisters are a rare sub-population of tumor cells that survive anti-cancer therapy and are thought to be a major cause of recurrence. These cells have been identified following both drug- and immune-therapy but are generally considered to be distinct entities. Since both pharmacological agents and immune cells often kill via apoptosis, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which in turn would yield a similar and reciprocal multi-agent resistant phenotype. Supporting this hypothesis, we indeed observed that IPCs acquired a reduced sensitivity to multiple drug classes and radiotherapy, suggesting non-immune mechanisms are important in the survival of cancer cells after immunotherapy. Likewise, DTPs developed not only a reduced sensitivity to multiple drug classes and radiotherapy, but also acquired a reduced sensitivity to T cell killing. Both IPCs and DTPs developed a decreased sensitivity to mitochondrial apoptosis. A sub-population of IPCs downregulated antigen and upregulated PD-L1. Intriguingly, in the IPCs that didnt employ these mechanisms of resistance, a greater decrease in sensitivity to mitochondrial apoptosis was observed, suggesting that the presence or absence of a resistance mechanism can exert selective pressures over the emergence of others. Targeting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common biological mechanisms underly survival of persisters, whether derived from immune or drug therapy, and offer an explanation for the acquired cross-resistance to these two types of therapies often observed in the clinic. HighlightsO_LIImmunotherapy persister cells (IPCs) are less sensitive to drugs and radiation. C_LIO_LIDrug tolerant persisters (DTPs) are less sensitive to radiation and CAR T cell attack. C_LIO_LIIPCs and DTPs are less sensitive to mitochondrial apoptosis. C_LIO_LITargeting anti-apoptotic dependencies helps eliminate IPCs/DTPs. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/641492v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@fe98b4org.highwire.dtl.DTLVardef@db7bfdorg.highwire.dtl.DTLVardef@1a94469org.highwire.dtl.DTLVardef@1ca6b2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Analysis of the polar residues located at the head domain of focal adhesion protein vinculin under the presence of the Shigella effector IpaA and its possible implications during in vivo mechanotransduction

Vinculin is a protein associated to linking adhesion receptors facing the outside of cells and reinforcing them by linking its intracellular domain of those receptors or, in the case of Cell-Matrix adhesions, to bind to a first level adaptor protein such as talin. The structural organization of vinculin allows it to bind on one part to specific amphipathic motifs collectively designated as vinculin binding sites (VBS), to a set of different vinculin coactivators or actin regulators, and finally a domain responsible to constantly bind to F-actin in a catch bond manner. However, the ability of vinculin to effectively bind all of those intracellular partners, is highly dependent on its structural organization. Which is critically dependent on its ability to respond to mechanical tension on the molecule itself and not necessarily to its binding capacity to VBSs and complementary activators. This is recognized as the combinatorial model of activation. Nonetheless, Shigellas IpaA effector protein is able to mimic the conformational changes associated with the ones associated with the mechanical deformation of the molecule. This model of vinculin activation is designated as the non-combinatorial model, as the presence of a single activation-partner is enough to get the same effect. This work is devoted to dig in further to develop the previous work from this lab, as we have been able to characterize the in vitro and in vivo effects of Shigellas IpaA-Cterm region as the one responsible for both inducing conformational changes in solution, as well as the formation of super-stable adhesion, associated to maturity markers as VASP and alpha actinin. Additionally the IpaA-Cterm transfection renders those cells with the ability to maintain the adhesion structures stable and even resist the action of actomyosin relaxing molecules. Which renders them as mechanically-independent adhesions. We found that residue substitution at the surface of D1 and D2 interphase, (as well as residues maintaining the D2 domain helical bundles folded), might participate in the maintaining the structural integrity and interdomain interaction during force dependent as revealed by its ability to form protein complexes in vitro and under force-independent settings, as the morphology of cellular adhesions is altered in a way different from the previously reported targeting only the D1-D5 interaction.

biochemistry↗

bioRxiv2022

The BRCA1 isoform, BRCA1-IRIS, operates independently of the full-length BRCA1 in the Fanconi anemia pathway

The tumor suppressor BRCA1 encodes multiple protein products including the canonical BRCA1-p220 (p220), which plays important roles in repair of diverse types of DNA damage. However, contributions of other BRCA1-encoded protein isoforms to DNA damage repair are less clear. Here, we report that the BRCA1-IRIS (IRIS) isoform has critical functions in the Fanconi anemia (FA) pathway and in repair of DNA interstrand crosslinks (ICLs). Loss of IRIS expression sensitizes cells to ICLs and impairs ICL repair. ICL formation stimulates association of IRIS with both FANCD2 and the FA core complex, which promotes FANCD2 recruitment to damage sites. The unique, BRCA1 intron 11-encoded C-terminal tail of IRIS is required for complex formation with FANCD2 and for ICL-inducible FANCD2 mono-ubiquitylation. Collectively, our findings reveal that IRIS plays an essential role, upstream of the p220-directed HR, in the FA pathway through a previously unrecognized mechanism that depends on the IRIS-FANCA-FANCD2 interaction. HighlightsO_LIBRCA1 splicing isoform BRCA1-IRIS is required for interstrand crosslink (ICL) repair. C_LIO_LIBRCA1-IRIS interacts with FANCD2 and promotes its recruitment to sites of ICL damage. C_LIO_LIBRCA1-IRIS, but not BRCA1-p220, promotes ICL-inducible FANCD2 mono-ubiquitylation. C_LIO_LIThe unique C-terminal tail of BRCA1-IRIS is essential for its function in ICL repair. C_LI

molecular biology↗