2025 Hyper Recent •CC0 1.0 Universal

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

Access Preprint From Server
May 8th, 2025
Version: 1
School of Chinese Medicine, Hong Kong Baptist University
cancer biology
biorxiv

Metabolic modulation of intratumoral cholesterol with gut microbiota for the treatment of colorectal cancer

Wu, J.Open in Google Scholar•Lai, Y.Open in Google Scholar•Li, J.Open in Google Scholar•Zhai, L.Open in Google Scholar•Asthana, P.Open in Google Scholar•Chen, L.Open in Google Scholar•Chen, M.Open in Google Scholar•Chen, B.Open in Google Scholar•Gurung, S.Open in Google Scholar•Lyu, J.Open in Google Scholaret al.

Excess cholesterol is positively correlated with colorectal cancer (CRC). Current therapeutic strategies for modulating cholesterol levels in CRC are limited and often come with complications. Here, we demonstrated that microbiome shunting of intestinal cholesterol to anticancer metabolites is a safe and applicable therapeutic approach for CRC. By screening major microbial metabolic products of cholesterol, we found that 4-cholesten-3-one (4-C-3) was selectively depleted in fecal samples and tumor tissues of patients with CRC. 4-C-3 exhibits strong antitumor effects on human CRC cell lines, patient-derived organoids, and patient-derived xenograft (PDX) models. Mechanistically, 4-C-3 suppresses CRC tumorigenesis by dually targeting the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homologue (KRAS). 4-C-3 directly binds to EGFR, blocking its signal transduction by inhibiting the binding of EGFR ligands. Additionally, 4-C-3 inhibits oncogenic KRAS variants, such as KRASG12D, by suppressing nucleotide exchange activity and effector engagement. By targeting both EGFR and KRAS, 4-C-3 reduces primary resistance to anti-EGFR therapies caused by KRAS mutations in CRC. As a proof-of-concept study, we showed that delivery of 4-C-3 by Oscillibacter ruminantium, a 4-C-3-producing commensal bacterium that is reduced in CRC patients, or a nonpathogenic Escherichia coli strain engineered to specifically convert intestinal cholesterol into 4-C-3, removed intratumoral cholesterol and led to rapid tumor regression in multiple models of CRC. These results suggest that microbial therapies for restoring intestinal cholesterol homeostasis represent a new therapeutic avenue for CRC.

Similar Papers

biorxiv
Fri May 09 2025
Deep learning inference of cell type-specific gene expression from breast tumor histopathology
Cell type-specific gene expression from single-cell RNA sequencing (RNA-seq) is valuable for breast cancer precision oncology but available cohorts are still limited due to its high cost. Deconvolution methods infer cell type-specific expression from bulk RNA-seq at a lower cost, yet expenses and processing time of bulk RNA-seq are also non-negligible and limit their application too. To address th...
Wang, A. T.
•
Dhruba, S. R.
•
Wang, K.
•
Campagnolo, E. M.
...•
Ruppin, E.
biorxiv
Fri May 09 2025
Single cell spatial transcriptomics identifies coordinated cellular programs associated with good prognosis in microsatellite stable colorectal cancer
It has been reported that microsatellite instable (MSI) tumors in colorectal cancer (CRC) exhibit stronger anti-tumor responses than microsatellite stable (MSS) tumors. Analyzing scRNA-seq data from 185 CRC patients we found that immune, structural, and cancer cells in MSS tumors with high numbers of tumor-infiltrating CD8 T cells and macrophages (TAMs; CD8hiTAMhi) and CD8lowTAMhi tumors were enri...
Karlsen, V. T.
•
Majid, U.
•
Lindholm, H. T.
•
Umu, S. U.
...•
Jahnsen, F. L.
biorxiv
Fri May 09 2025
Improved Tumor Blood Flow Enhances the Abscopal Effect: Preclinical Assessment in Mice Treated with Combined Radiation and PD-1 Blockade Therapy
The abscopal effect, where localized radiation therapy induces regression of distant metastatic lesions through immune activation, shows promise for treating metastatic cancer but occurs inconsistently. Here we demonstrate that tumor perfusion critically influences systemic immune responses to combination therapy with radiation and PD-1 blockade. Using multimodal imaging including DCE-MRI, EPR oxi...
Yamashita, K.
•
Brender, J. R.
•
Saida, Y.
•
Otowa, Y.
...•
Kishimoto, S.
biorxiv
Fri May 09 2025
BRAFV600E-Driven Lung Tumorigenesis Requires Ligand-Mediated Activation of ERBB Receptor Signaling
Secretion of ligands of the human epidermal growth factor (EGFR) family of receptors or erythroblastic leukemia viral oncogene family (ERBB1-4) is a feature common to many cancer cells. However, our understanding of the role of autocrine ligands in the aberrant behavior of cancer remains incomplete. Here we demonstrate that, in numerous preclinical models of lung tumorigenesis, BRAFV600E signaling...
Dacheux, M.
•
Wu, M.-J.
•
Scherzer, M. T.
•
Nillson, M.
...•
Vaishnavi, A.
biorxiv
Fri May 09 2025
SRSF3 knockdown-induced cellular senescence as a possible therapeutic strategy for non-small cell lung cancer
Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases only consist of about 50% in the western populations. This study, for the first time in NSCLC cells including those without a targetable TK mutation, explores a tumor-suppressive activity of siRNA knockdown of a splicing factor SRSF3, which was report...
Nakamichi, S.
•
von Muhlinen, N.
•
Yamada, L.
•
Melamed, J. R.
...•
Harris, C. C.
biorxiv
Fri May 09 2025
Differential DNA damage response to WRN inhibition identifies a targetable vulnerability in ARID1A-mutated cancers
ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancers. However, effective clinical treatments for patients with this mutation are limited, highlighting a demand for new therapeutic strategies. Here, we establish Werner syndrome ATP-dependent helicase (WRN) as a critical vulnerability target in ARID1A-mutated cancers. Upon genetic and pharmacological in...
Kim, J.
•
Oh, J.
•
Jang, D.
•
Shin, S.
...•
Cho, S.-Y.
biorxiv
Fri May 09 2025
Bone marrow lymphocyte dynamics during chemotherapy in pediatric acute myeloid leukemia
A better understanding of lymphocyte dynamics during current treatment regimens in pediatric AML is urgently needed to understand whether the application of bispecific T-cell-engagers (BiTEs) during periods of low tumor burden could be a viable treatment strategy. In this study, we found that induction 1, comprising mitoxantrone-etoposide-cytarabine in nearly all patients (as part of the NOPHO-DBH...
Koedijk, J. B.
•
Barneh, F.
•
Meesters-Ensing, J. I.
•
van Tuil, M.
...•
Heidenreich, O.
biorxiv
Fri May 09 2025
Multiomic profiling of hypoxic glioblastoma stem cells reveals expansion of subpopulations with distinct epigenetic and CNV profiles
Glioblastoma is characterized by extensive intratumoral heterogeneity driven by dynamic microenvironmental cues such as hypoxia. While transcriptional and epigenetic variability have been separately linked to hypoxia responses, the integrated impact of hypoxia on gene regulation and clonal architecture in glioblastoma stem cells (GSCs) remains poorly defined. We applied single-nucleus multiomics n...
Corseri, A.
•
Moore, T. W.
•
Szczepanski, N.
•
Hwang, H.
...•
Tapinos, N.
biorxiv
Thu May 08 2025
Hypomethylating agents induce epigenetic and transcriptional heterogeneity with implications for AML cell self-renewal.
DNA hypomethylating agents (HMAs) are used to treat acute myeloid leukemia (AML) and myelodysplasia patients who are unsuitable for intensive chemotherapy. However, low response rates and therapy-resistant relapse remain significant challenges. To improve outcomes, we must understand how AML cells survive HMA treatment and continue to proliferate following therapy. We combine single-cell multiomic...
Bond, D. R.
•
Burnard, S. M.
•
Uddipto, K.
•
Hunt, K. V.
...•
Lee, H. J.