KRAS Withdrawal in Cholangiocarcinoma Leads to Immune Infiltration and Tumor Regression

Youwei Qiao; Matthew F Yee; Chaitanya N Parikh; Boyang Ma; Yueying Cao; Yu-Huan Shih; Joae Qiong Wu; Marcus Ruscetti; Shun-Qing Liang; Wen Xue

doi:10.1002/advs.202511312

KRAS Withdrawal in Cholangiocarcinoma Leads to Immune Infiltration and Tumor Regression

Adv Sci (Weinh). 2025 Dec 3:e11312. doi: 10.1002/advs.202511312. Online ahead of print.

Authors

Youwei Qiao¹, Matthew F Yee¹, Chaitanya N Parikh², Boyang Ma², Yueying Cao¹, Yu-Huan Shih³, Joae Qiong Wu³, Marcus Ruscetti², Shun-Qing Liang^{1

4}, Wen Xue^{1

2

5

6}

Affiliations

¹ RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
² Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
³ Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁴ Department of Medicine, University of Minnesota Twin Cities, Minneapolis, MN, 55455, USA.
⁵ Department of Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
⁶ Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

PMID: 41332325
DOI: 10.1002/advs.202511312

Abstract

Cholangiocarcinoma (CCA) is a liver cancer subtype with poor survival rates. KRAS mutations are found in 15-40% of CCA, representing a new potential treatment target. Whether KRAS inhibition leads to CCA tumor regression is unknown, partly due to the lack of conditional animal models. A conditional TRE.Kras^G12D/Trp53 knock-out (TKP) CCA mouse model is engineered using the transposon system and CRISPR-Cas9. Withdrawal of Kras^G12D results in >90% tumor regression by day 7, accompanied by infiltration and enrichment of activated CD8⁺ T cells, shown by IHC, co-IF staining, and single-cell RNA-Seq. Bulk RNA-Seq of TKP cell line suggested that Kras^G12D withdrawal stimulates the transforming growth factor beta pathway and induces senescence. Cytokine array characterizes the secretion of pro-inflammatory factors, including IL-15 and CCL17. Lentiviral overexpression of murine IL-15 and CCL17 delays CCA tumor progression in a syngeneic transplant model. Consistently, expression of IL-15 resulted in blockade of tumor progression in the TKP CCA model. These findings highlight the importance of oncogenic Kras in CCA tumor maintenance and underscore KRAS inhibition as a potential therapeutic approach for CCA.

Keywords: KRAS inhibition; biliary malignancy; cholangiocarcinoma; oncology.

Abstract

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