Biology subjects

Hanker, A. B.

Publications and source records attributed to Hanker, A. B..

4 recordsLinked to original sources

bioRxiv2026

Tumor control of lysosomal acidification promotes lipoprotein assimilationand ferroptosis resistance

Lysosomes are acidic organelles that fuel cancer progression by facilitating nutrient acquisition and metabolic adaptation, yet the determinants through which cancer cells sustain specialized lysosomal functions are not fully delineated. Notably, assimilation of dietary antioxidants within lipoproteins, a lysosome-dependent process, protects tumors from ferroptosis, an oxidative form of cell death, raising the possibility that tumors evolve mechanisms to enhance this process. Here, we applied genetic screens to identify regulators of lysosome-dependent lipoprotein assimilation and ferroptosis resistance and identified ZNF217, a frequently amplified transcriptional regulator in human cancers, as a driver of tumor lysosomal function and ferroptosis resistance. ZNF217 promoted lipoprotein assimilation through transcriptional maintenance of RAB11FIP4, an endolysosomal protein. Loss of either ZNF217 or RAB11FIP4 impaired lysosomal acidification across multiple cancer types, leading to defective lipoprotein assimilation, increased lipid peroxidation, ferroptosis sensitivity, and impaired tumor growth. Mechanistically, RAB11FIP4 boosts lysosomal acidity through maintenance of RAB7A activity. Finally, disruption of ZNF217 in breast cancer cell lines and patient-derived organoids, a tumor context linked to ZNF217 expression, reduced lysosomal acidity and impaired cancer growth through increased ferroptosis sensitivity. Together, we identify transcriptional regulation of lysosomal acidification as a key metabolic adaptation that enables extracellular antioxidant acquisition and tumor progression.

cancer biology↗

bioRxiv2023

Mapping Cell-to-cell Interactions from Spatially Resolved Transcriptomics Data

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently, through the introduction of spatially resolved transcriptomics technologies (SRTs), especially those that achieve single cell resolution. However, significant challenges remain to analyze such highly complex data properly. Here, we introduce a Bayesian multi-instance learning framework, spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight spacias power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates, and most importantly the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of spacia for all three commercialized single cell resolution ST technologies: MERSCOPE/Vizgen, CosMx/Nanostring, and Xenium/10X. Spacia unveiled how endothelial cells, fibroblasts and B cells in the tumor microenvironment contribute to Epithelial-Mesenchymal Transition and lineage plasticity in prostate cancer cells. We deployed spacia in a set of pan-cancer datasets and showed that B cells also participate in PDL1/PD1 signaling in tumors. We demonstrated that a CD8+ T cell/PDL1 effectiveness signature derived from spacia analyses is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. We revealed differential spatial interaction patterns between {gamma}{delta} T cells and liver hepatocytes in healthy and cancerous contexts. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.

bioinformatics↗

bioRxiv2022

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.

cancer biology↗

bioRxiv2020

A Single-Objective Light-Sheet Microscope with 200 nm-Scale Resolution.

We present an Oblique Plane Microscope that uses a bespoke glass-tipped tertiary objective to improve the resolution, field of view, and usability over previous variants. Owing to its high numerical aperture optics, this microscope achieves lateral and axial resolutions that are comparable to the square illumination mode of Lattice Light-Sheet Microscopy, but in a user friendly and versatile format. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and Natural Killer-mediated cytotoxicity. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through confined spaces within a microfluidic device, subcellular photoactivation of Rac1, diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz, and large field of view imaging of neurons, developing embryos, and centimeter-scale tissue sections.

biophysics↗