# A vicious cycle of pyroptotic cancer cells and fibroblasts fuels chemoresistance

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2021 · $390,397

## Abstract

PROJECT SUMMARYTO APPLICATION
This application is in direct response to the RFA-CA-19-049 “Revision Applications for Mechanisms of Cancer
Drug Resistance”, to investigate a non-classical mechanism driving the chemoresistance of locally advanced
bladder carcinomas. Advanced bladder cancer claims approximately 18,000 deaths annually in the United
States; yet, funding and research devoted to this cancer-type are significantly under-proportioned. A major
clinical setback for bladder cancer treatment lies in the poor patient response towards chemotherapy with
treatments providing only a dismal 5% improvement in overall survival. Thus, the goal of this application aims
to understand the less-studied biology, i.e., cancer cell-extrinsic mechanisms, causing chemotherapy drug
resistance. The success of chemotherapy is long thought to depend on its direct cytotoxic effects upon tumor
cells and this has attracted much research interest in the past decades. However, there is growing evidence,
as shown by our own research and others, that successful chemotherapy is also dependent on: 1)
feedforward signals between dying cancer cells and the stromal fibroblast microenvironment, and 2) the
active role(s) of collagens secreted from cancer associated fibroblasts to serve as a protective niche for
chemoresistant cancer cells. Our proposal will leverage existing patient-derived cancer associated fibroblasts
and patient-derived primary tumor cultures/xenografts developed from the parent grant NCI CA175397,
which allow us to venture into a new research direction: i.e., how cell death associated release of extracellular
factors impacts the fibrotic environment, consequently serves as a protective niche to fuel chemoresistant
cancer cells? This proposal is innovative to elucidate the intricate feedforward loops between dying cancer
cells, cancer-associated fibroblasts, and residual cancer stem cells during the emergence of
chemoresistance. The success of this study will be innovative and impactful to challenge the current
paradigm that chemotherapy drug resistance is primarily driven by cancer cell-intrinsic properties. Indeed,
success of our proposal will establish an original concept: Dying cancer cells provide feedforward signals to
cultivate a collagen-rich fibrotic environment, consequently initiating a “vicious cycle” of epithelial-stromal
feedforward signaling loop to fuel chemoresistance. Also, our proposal will provide new insights into the
rational design of future intervention strategies to “break” this vicious cycle, and thus, improve chemotherapy
response. Such a concept likely extends beyond bladder carcinomas into other cancer types.

## Key facts

- **NIH application ID:** 10213480
- **Project number:** 3R01CA175397-07S1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Keith Syson Chan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,397
- **Award type:** 3
- **Project period:** 2013-09-30 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213480

## Citation

> US National Institutes of Health, RePORTER application 10213480, A vicious cycle of pyroptotic cancer cells and fibroblasts fuels chemoresistance (3R01CA175397-07S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10213480. Licensed CC0.

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