Targeting the YAP-mediated stromal signaling unlocks chemoresistance in a human organoid fibrosis model
Duoer Xiong1,2, Qihang Zheng1,2, Wei Chen3
1School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, No. 66, Gongchang Road., Guangming District, Shenzhen, Guangdong 518107, People's Republic of China.
Abstract:
The fibrotic stroma drives tumor progression and impairs therapy, but existing models fail to capture its dual barrier and signaling roles, limiting mechanistic understanding and therapeutic development. To address this, we established a patient-derived fibrotic tumor model that recapitulates key pathophysiological features: extracellular matrix remodeling, substantial tissue stiffening (12-fold increase), and pro-malignant transcriptomic reprogramming. This model demonstrated microenvironment-mediated chemoresistance, increasing the area under the dose-response curve by 1.3-fold and suppressing oxaliplatin-induced apoptosis. Although stiffening delayed drug penetration, barrier disruption did not restore sensitivity. Instead, stiffness inactivated the Hippo pathway, activating YAP as the key chemoprotection driver. YAP inhibition restored drug sensitivity without altering stiffness, revealing a targetable biochemical mechanism independent of the physical barrier. Using this insight, we designed a sequential regimen in which nintedanib preconditioning precedes chemotherapy, achieving near-complete tumor eradication (<5% tumor viability). This work provides a physiological model of stromal biology and a mechanism-guided strategy to overcome microenvironment-mediated chemoresistance.
Insights
Fibrotic tumor stroma hinders cancer therapy by creating physical barriers and altering cell signaling. Targeting the YAP pathway and using nintedanib preconditioning can overcome this resistance, leading to effective tumor eradication.
Area of Science:
- Oncology
- Biomedical Engineering
- Cancer Biology
Background:
- The fibrotic stroma in tumors impedes cancer progression and treatment efficacy.
- Current models inadequately represent the complex barrier and signaling functions of the fibrotic microenvironment.
- This limitation hinders mechanistic insights and the development of novel therapeutic strategies.
Purpose of the Study:
- To develop a patient-derived fibrotic tumor model that accurately reflects key pathological features.
- To investigate the mechanisms of chemoresistance mediated by the fibrotic tumor microenvironment.
- To identify and validate novel therapeutic strategies to overcome stromal-mediated chemoresistance.
Main Methods:
- Established a patient-derived fibrotic tumor model with features like ECM remodeling and increased tissue stiffness.
- Assessed chemoresistance, drug penetration, and apoptosis induction in the model.
- Investigated the role of the Hippo-YAP pathway and tissue stiffness in chemoresistance.
- Evaluated a sequential therapeutic regimen involving nintedanib preconditioning and chemotherapy.
Main Results:
- The model exhibited significant tissue stiffening (12-fold increase) and transcriptomic reprogramming.
- Microenvironment-mediated chemoresistance was observed, with a 1.3-fold increase in the dose-response curve and suppressed oxaliplatin-induced apoptosis.
- Tissue stiffness inactivated the Hippo pathway, activating YAP, which was identified as a key driver of chemoprotection.
- YAP inhibition restored drug sensitivity independently of physical barrier effects.
- A sequential nintedanib and chemotherapy regimen achieved near-complete tumor eradication (<5% tumor viability).
Conclusions:
- The developed patient-derived model offers a physiological platform for studying stromal biology.
- YAP activation by tissue stiffness is a critical mechanism of chemoresistance, targetable independent of physical barrier disruption.
- A mechanism-guided sequential therapy combining nintedanib and chemotherapy shows significant potential for overcoming fibrotic tumor resistance.
