Biology subjects

Kardosh, A.

Publications and source records attributed to Kardosh, A..

7 recordsLinked to original sources

bioRxiv2026

ACCREDIT: A Quality-Aware Agentic Engine for Cell-resolved Cross-modal Image Registration with Dynamic Iterative Tuning

Spatial omics across complementary modalities is transforming our understanding of tissue architecture. Realizing this potential requires accurate and robust registration of cross-platform molecular images with hematoxylin-and-eosin (H&E) sections, the primary morphological reference for pathology. Existing methods, however, often fail silently when image orientation is unknown, image contrast is inverted, or tissue overlap is incomplete, producing erroneous registrations without alerting users or attempting recovery. Here, we present ACCREDIT, a quality-aware agentic framework that redefines cross-modal registration as an adaptive decision-making process rather than a one-shot computation. ACCREDIT combines deterministic registration pipelines with a reference-free composite quality score that automatically evaluates registration quality and rejects plausible but biologically incorrect registrations. When registration quality is insufficient, a large language model (LLM)-based rescue agent autonomously diagnoses failure modes and selects targeted recovery strategies, while an optional strategy-learning module captures expert-validated corrections for future reuse. Across Xenium, CODEX, cell-boundary, and IHC-to-H&E registration tasks, ACCREDIT outperformed competing methods by detecting registration failures and improving alignment quality through automated recovery and rescue. Ultimately, ACCREDIT enables robust integration of histology and spatial molecular profiling, providing a foundation for translating spatial omics into routine H&E-based pathology workflows.

bioinformatics↗

bioRxiv2026

Tissue-resident memory B cells augment local anti-cancer immunity via IgA

Tissue-resident memory B cells (BRM) provide powerful localized protection against microbial infection in barrier tissues. It is unknown if analogous BRM populations survey solid tumors and contribute to anti-cancer immunity. We profiled B cells from patients with colorectal cancer and cutaneous basal cell carcinoma and identified a CD69+ memory B cell population consistent with a tissue-resident phenotype. Integrative analysis of transcriptomic datasets identified an optimized signature enriched across cancer types. Tumor infiltrating BRM-like cells preferentially exhibited autoreactivity and their signature correlated with patient outcomes and response to immunotherapy. Skin and lung targeted vaccination established localized BRM that provided IgA dependent organ specific protection upon tumor challenge in murine models. These findings establish BRM as an active component of anti-cancer immunity via preferential reactivity to tumor associated self-antigens.

immunology↗

bioRxiv2026

Cyclic immunofluorescence platform using photocleavable linkers for direct antibody labeling enables cancer phenotyping

Advances in spatial proteomics through the development of multiplexed immunostaining platforms have facilitated analyses with increasing cellular and molecular granularity. However, currently available approaches are limited by harsh conditions for signal removal, restricting the number of antigens that can be probed in a single specimen without significant alterations to sample quality and structure. Here we present an approach for direct labeling of primary antibodies with fluorophores using a photocleavable linker (PCL) with a polyethylene glycol spacer (PEG) to enable cyclic immunofluorescence (cyCIF) with gentle signal removal conditions. Our innovative approach uses directly labeled primary antibodies to enhance staining specificity and cyclic immunostaining efficiency, while minimizing nonspecific background signal. Additionally, through integration of the PCL, this approach facilitates gentle cleavage of antibody conjugated fluorophore, preserving sample integrity over multiple rounds of staining. Direct PEG-PCL antibody labeling will promote greater multiplexing by minimizing specimen damage and allow for quantitative analyses of cyCIF spatial data. We demonstrate that cyCIF with PEG-PCL conjugated antibodies can be applied across a variety of cancer subtypes to identify and characterize rare neoplastic cell populations in both tumor tissue and fragile peripheral blood specimens.

biochemistry↗

bioRxiv2026

Evaluation and application of chemical decrosslinking in the context of histopathological spatial proteomics

Laser capture microdissection (LCM) - based spatial mass spectrometry proteomics is a rapidly emerging technique with strong potential for use in formalin-fixed, paraffin-embedded (FFPE) tissues. Several sample-preparation methods have been developed to decrosslink FFPE proteins for spatial proteomics; however, residual crosslinks often remain, and depth can remain impaired relative to fresh frozen tissue samples. To increase proteome coverage in spatially resolved LCM-FFPE samples, we investigated a panel of chemical compounds with the potential to catalyze the decrosslinking of nucleophilic functional groups on proteins. Systematic screening and optimization of temperature, incubation time, and reagent concentration led to the identification of 3,4-diaminobenzoic acid as an effective agent for improving proteome coverage in FFPE pancreatic tissue. This compound could boost precursor identifications by more than 10% at both reduced (70 {degrees}C) and high (90 {degrees}C) temperatures. Application of this chemical-decrosslinking strategy to a pancreatic ductal adenocarcinoma tissue section enabled the identification of numerous cell-type-enriched proteins with clinical and therapeutic relevance. Taken together, our findings show that chemical decrosslinking can increase proteome coverage in FFPE tissues, thereby advancing our understanding of tissue microenvironments in physiological and pathological contexts.

cancer biology↗

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2024

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFN{gamma} pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFN{gamma} pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

cancer biology↗

bioRxiv2022

Ongoing Replication Stress Response and New Clonal T Cell Development Discriminate Between Liver and Lung Recurrence Sites and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

Background and AimsMetastatic pancreatic adenocarcinoma (mPDAC) is lethal, yet a subset of patients who have metastatic disease that spreads only to the lung have better outcomes. We identified unique transcriptomic and immune features that distinguish patients who develop metastases in the liver (liver cohort) versus those with lung-avid but liver-averse mPDAC (lung cohort). MethodsWe used clinical data from the Oregon Pancreas Tissue Registry to identify PDAC patients with liver and/or lung metastases. Gene expression and genomic alteration data from 290 PDAC tumors were used to identify features unique to patients from the liver and lung cohorts. In parallel, T cell receptor sequencing data from 289 patients were used to identify immune features unique to patients in the lung cohort. ResultsLung cohort patients had better survival outcomes than liver cohort patients. Primary tumors from patients in the liver cohort expressed a novel gene signature associated with ongoing replication stress (RS) response predictive of poor patient outcome independent from known subtypes. In contrast, patients with tumors lacking the RS response signature survived longer, especially if their tumors had alterations in DNA damage repair genes. A subset of patients in the lung cohort demonstrated new T cell clonal development in their primary and metastatic tumors leading to diverse peripheral blood TCR repertoires. ConclusionLiver-avid metastatic PDAC is associated with an ongoing RS response, whereas tumors lacking the RS response with ongoing T cell clonal responses may have unique vulnerabilities allowing long-term survival in patients with lung-avid, liver-averse metastatic PDAC.

cancer biology↗