Biology subjects

Chua, H.

Publications and source records attributed to Chua, H..

3 recordsLinked to original sources

bioRxiv2024

Modelling oxaliplatin resistance in colorectal cancer reveals a SERPINE1-based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype

Drug resistance and distant metastases are major contributors to mortality in colorectal cancer (CRC). Here we investigate mechanisms underlying acquired resistance to oxaliplatin, a first-line, standard-of-care CRC treatment. We generated oxaliplatin-resistant CRC tumor cells with clinically relevant dosing regimen, which displayed enhanced metastatic potential. Transcriptomic and phenotypic analyses revealed a critical function for cholesterol biogenesis in modulating TGF-{beta} signaling activity, which in turn regulates SERPINE1 expression, a gene we identified as a key player in promoting drug resistance and metastasis. Additionally, we uncovered a SERPINE1-associated nine-gene expression signature, RESIST-M, that can predict overall and relapse-free survival (RFS) in clinical cohorts and is able to stratify patients into CMS4/iCMS3-fibrotic CRC-subtypes, underscoring its clinical utility. Using mouse tumor models, we provide further evidence that targeting SERPINE1 and cholesterol biogenesis can be viable approaches to re-sensitize the resistant pro-metastatic CRC cells to oxaliplatin. This study not only elucidates the molecular underpinnings of drug resistance and metastasis in primary CRC, but also offers prognostic and therapeutic strategies to guide clinical management of the disease. SignificanceThis study reveals critical resources and insights on oxaliplatin resistance and metastasis in CRC via a novel TGF-{beta} cholesterol axis. We generated improved oxaliplatin-resistant models that enabled identification of a prognostic SERPINE1-based gene signature to predict oxaliplatin resistance-induced metastasis in CRC. This gene signature derived from our models showed that the models can mimic CMS-4/iCMS-fibrotic-like metastatic CRC patients. We validated therapeutic candidates targeting CMS-4/iCMS-fibrotic-like metastatic CRC cells which can reverse drug resistance and metastasis.

cancer biology↗

bioRxiv2024

Foundry-fabricated dual-color nanophotonic neural probes for photostimulation and electrophysiological recording

SignificanceCompact tools capable of delivering multicolor optogenetic stimulation to deep tissue targets with sufficient span, spatiotemporal resolution, and optical power remain challenging to realize. Here, we demonstrate foundry-fabricated nanophotonic neural probes for blue and red photostimulation and electrophysiological recording, which use a combination of spatial multiplexing and on-shank wavelength-demultiplexing to increase the number of on-shank emitters. AimWe demonstrate Si photonic neural probes with 26 photonic channels and 26 recording sites, which were fabricated on 200-mm diameter wafers at a commercial Si photonics foundry. Each photonic channel consists of an on-shank demultiplexer and separate grating coupler emitters for blue and red light, for a total of 52 emitters. ApproachWe evaluate neural probe functionality through bench measurements and in vivo experiments by photostimulating through 16 of the available 26 emitter pairs. ResultsWe report neural probe electrode impedances, optical transmission, and beam profiles. We validated a packaged neural probe in optogenetic experiments with mice sensitive to blue or red photostimulation. ConclusionsOur foundry-fabricated nanophotonic neural probe demonstrates dense dual-color emitter integration on a single shank for targeted photostimulation. Given its two emission wavelengths, high emitter density, and long site span, this probe will facilitate experiments involving bidirectional circuit manipulations across both shallow and deep structures simultaneously.

neuroscience↗

bioRxiv2023

Implantable nanophotonic neural probes for integrated patterned photostimulation and electrophysiology recording

Optogenetics has transformed neuroscience by allowing precise manipulation of neural circuits with light [1-5]. However, a central difficulty has been to deliver spatially shaped light and record deep within the brain without causing damage or significant heating. Current approaches form the light beam in free space and record the neural activity using fluorescence imaging or separately inserted electrodes [6-9], but attenuation limits optical penetration to around 1 mm of the brain surface [10]. Here, we overcome this challenge with foundry-fabricated implantable silicon neural probes that combine microelectrodes for electrophysiology recordings with nanophotonic circuits that emit light with engineered beam profiles and minimal thermal impact. Our experiments reveal that planar light sheets, emitted by our neural probes, excited more neurons and induced greater firing rate fatigue in layers V and VI of the motor and somatosensory cortex of Thy1-ChR2 mice at lower output intensities than low divergence beams. In the hippocampus of an epilepsy mouse model, we induced seizures, a network-wide response, with light sheets without exceeding the[~] 1{whitebullet}C limit for thermally induced electrophysiological responses [11-13]. These findings show that optical spatial profiles can be tailored for optogenetic stimulation paradigms and that the probes can photostimulate and record neural activity at single or population levels while minimizing thermal damage to brain tissue. The neural probes, made in a commercial silicon photonics foundry on 200-mm silicon wafers, demonstrate the manufacturability of the technology. The prospect of monolithically integrating additional well-established silicon photonics devices, such as wavelength and polarization multiplexers, temperature sensors, and optical power monitors, into the probes holds the potential of realizing more versatile, implantable tools for multimodal brain activity mapping.

bioengineering↗