2025 Hyper Recent •CC0 1.0 Universal

This work is dedicated to the public domain. No rights reserved.

Access Preprint From Server
April 6th, 2025
Version: 1
Icahn School of Medicine at Mount Sinai
cancer biology
biorxiv

Learning the cellular origins of cancer using single-cell chromatin landscapes

Bairakdar, M. D.Open in Google Scholar•Giotti, B.Open in Google Scholar•Lee, W.Open in Google Scholar•Stancl, P.Open in Google Scholar•Wagenblast, E.Open in Google Scholar•Hambardzumyan, D.Open in Google Scholar•Polak, P.Open in Google Scholar•Karlic, R.Open in Google Scholar•Tsankov, A.Open in Google Scholar

Deciphering the cellular history of different cancers is critical for understanding tumor development and improving diagnostic and therapeutic strategies in oncology. Previous studies have shown that chromatin accessibility of the normal cell of transformation (COT) is a major determinant of a cancer\'s mutational landscape. We leveraged single-cell chromatin accessibility data from 559 healthy cell subsets to predict the COT across 36 cancer subtypes, providing unprecedented scale and resolution into the cellular beginnings of cancers. Our machine learning model predicts the COT with high robustness and accuracy, confirming both the known anatomical and cellular origins of numerous cancers, often at cell subset resolution. Unexpectedly, our work challenges traditional views that small cell lung cancer arises from neuroendocrine cells, opening new avenues for research. Our study also highlights different cellular trajectories for histological subtypes and a metaplastic state during tumorigenesis for multiple gastrointestinal cancers, which have important implications for cancer prevention, early detection, and treatment stratification.

Similar Papers

biorxiv
Mon Apr 07 2025
Bimodal genomic approach predicting Semaphorin 7A (SEMA7A) as prognostic biomarker in adrenocortical carcinoma
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with high mortality and poor prognosis. To elucidate the genetic underpinnings of ACCs, we have analyzed the transcriptome data of 112 ACC tumor samples from patients enrolled in the TCGA and NCI. Among 72 bimodally expressed genes stratifying patients into prognostic groups, we focused on SEMA7A, as it encodes a glycosyl...
Dhall, A.
•
Taniyama, D.
•
Elloumi, F.
•
Luna, A.
...•
Pommier, Y.
biorxiv
Mon Apr 07 2025
Alectinib enhances response to RBM39 degradation via SRPK1 inhibition
RNA splicing is a critical process in gene expression regulation and RNA splicing factors are increased in expression in many cancers. We have previously demonstrated that the molecular glue indisulam degrades RNA splicing factor RBM39 producing aberrant splicing transcripts that is very effective in high-risk neuroblastoma and can potentiate the sensitivity to DNA damaging agents in ovarian high-...
Ma, Y.
•
Poon, E.
•
Jin, C.
•
Martins da Costa, B.
...•
Nijhuis, A.
biorxiv
Mon Apr 07 2025
Deep Learning-Driven Subtype Classification of Colorectal Cancer Using Histopathology Images for Personalized Medicine
Accurate and timely diagnosis of colorectal cancer is critical for improving patient outcomes. While histopathological examination remains the gold standard, it is labor-intensive and prone to inter-observer variability. This study investigates the application of deep learning, specifically ResNet and Swin Transformer V2 architectures, for automated CRC subtype classification using hematoxylin and...
Truong Le, T.
•
Nguyen-Truong, V.-T.
•
Trong Le Phan, N.
•
Duong Van Nhat, Q.
...•
Thi Quang, K.
biorxiv
Sun Apr 06 2025
XPC loss-of-function triggers melanomagenesis through CDKN2A downregulation
We identified a novel XPC variant, c.2420+5G>A (XPCvar), in siblings with multiple melanomas, inherited alongside c.779+1G>T, which results in an absent or disrupted protein. Despite this, they exhibited nucleotide excision repair (NER) deficits comparable to their unaffected parents, suggesting an NER-independent tumor suppressor function for XPC. XPC knockdown increased cell proliferation and tu...
Chelakkot, V. S.
•
Thomas, K.
•
Romigh, T.
•
Bernat, A.
...•
Arbesman, J.
biorxiv
Sun Apr 06 2025
Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas
High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source an...
Ruiz, C. F.
•
Ge, X.
•
McDonnell, R.
•
Agabiti, S. S.
...•
Muzumdar, M. D.
biorxiv
Sat Apr 05 2025
BEHAV3D Tumor Profiler to map heterogeneous cancer cell behavior in the tumor microenvironment
Intravital microscopy (IVM) enables live imaging of animals at single-cell resolution, offering essential insights into cancer progression. This technique allows for the observation of single-cell behaviors within their natural 3D tissue environments, shedding light on how genetic and microenvironmental changes influence the complex dynamics of tumors. IVM generates highly complex datasets that of...
Rios-Jimenez, E.
•
Zomer, A.
•
Collot, R.
•
Barrera Roman, M.
...•
Alieva, M.
biorxiv
Fri Apr 04 2025
Differential Adaptation and Remodeling of the Tumor Microenvironment in Breast Cancer Cells During the Stages of Brain Metastasis
Objective To integrate macro-transcriptomics and single-cell sequencing to analyze the differential gene expression between primary and brain metastatic breast cancer cells, as well as between active and dormant cancer cells within brain metastases, exploring their adaptation and remodeling abilities at different stages of brain metastasis. Methods Four public datasets were used: three mRNA microa...
Wu, X.
•
Zhang, Y.
•
Huang, Z.
•
Li, R.
biorxiv
Fri Apr 04 2025
Hypoxia-induced extracellular matrix changes are conserved in cancer and directly impact radiotherapy benefit
Our overarching aim was to determine how hypoxia affects the extracellular matrix (ECM). Transcriptomic analysis (21,941 patients; 10 cancer types) identified ECM remodelling as the predominant pathway affected by hypoxia. Multi-omics confirmed that hypoxia impacts ECM organisation and collagen degradation; 53 ECM genes were affected, of which 74% were HIF1/HIF2-regulated. Spatial transcriptomics ...
Guerrero Quiles, C.
•
Gonzalez Abalos, J.
•
Foussat, A. S.
•
Olympitis, A.
...•
West, C.
biorxiv
Fri Apr 04 2025
Mapping the spatial architecture of glioblastoma from core to edge delineates niche-specific tumor cell states and intercellular interactions
Treatment resistance in glioblastoma (GBM) is largely driven by the extensive multi-level heterogeneity that typifies this disease. Despite significant progress toward elucidating GBM\'s genomic and transcriptional heterogeneity, a critical knowledge gap remains in defining this heterogeneity at the spatial level. To address this, we employed spatial transcriptomics to map the architecture of the ...
Khan, S. M.
•
Wang, A. Z.
•
Desai, R. R.
•
McCornack, C. R.
...•
Petti, A. A.