# Investigating L1CAM-dependent stem cell regeneration in metastasis

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $256,819

## Abstract

PROJECT SUMMARY
Metastatic cancers invariably relapse due to the emergence of resistant subclones that are capable of self-
renewal, slow cell-cycling, tumor re-initiation and therapy resistance, termed metastasis stem cells (MetSCs).
Yet the molecular mechanisms MetSCs employ for survival and regrowth are poorly understood. Preliminary
data described in this proposal identify the cell-adhesion molecule cell adhesion molecule L1 (L1CAM) as a
critical target for suppressing metastatic relapse. Employing novel patient-derived organoid models of therapy-
resistant colorectal cancer (CRC) liver metastases, L1CAM+ cells in patient tumors are shown to selectively
regenerate organoids ex vivo. L1CAM is required for the regeneration of organoids in vitro, and the mouse
colon epithelium after colitis injury in vivo. Disruption of cell-cell contact in intact epithelial structures is
necessary and sufficient for L1CAM induction, with expression diminishing over time as the epithelium is
regenerated. We hypothesize that epithelial disintegrity induces L1CAM expression, which is required for the
survival and regrowth of cancer cells during invasion, metastasis and following therapy. The mechanisms that
induce L1CAM dependency during tumor progression will be defined (1) using patient-derived organoid models
of metastatic CRC to define the transcriptional regulation of L1CAM downstream of epithelial junction
dissociation and (2) using genetically engineered mouse models, cutting-edge organoid-derived orthotopic
rectal transplantation, and orthotopic liver and lung metastatic models in vivo to determine the role of L1CAM in
tumor initiation, local invasion, metastatic colonization and maintenance. The proposed investigations will
delineate signaling pathways by which tumor dissemination induces phenotypic plasticity and the emergence
of metastatic traits, and will pave the way for L1CAM-targeting drugs that inhibit metastasis regeneration. The
applicant, Dr. Karuna Ganesh, an Instructor in the Gastrointestinal Oncology Service at Memorial Sloan Kettering
Cancer Center (MSKCC), has delineated a 5-year career plan that builds upon her research background in
biochemistry and clinical training in medical oncology. This project will provide the ideal training for Dr. Ganesh
in using clinically representative, state-of-the-art patient-derived organoid and mouse models to dissect the
transcriptional and epigenetic regulation of metastasis. Dr. Ganesh will be mentored by Dr. Joan Massagué, an
internationally renowned expert in metastasis with a strong track record of training successful independent
physician scientists. The candidate's career development plan includes coursework, workshops, mentoring from
an interdisciplinary advisory committee comprising distinguished basic scientists and medical oncologists, and
research experience in the outstanding institutional environment of MSKCC, a center of excellence in
translational cancer research. Successful completion of ...

## Key facts

- **NIH application ID:** 9982809
- **Project number:** 5K08CA230213-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Karuna Ganesh
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $256,819
- **Award type:** 5
- **Project period:** 2018-08-13 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982809

## Citation

> US National Institutes of Health, RePORTER application 9982809, Investigating L1CAM-dependent stem cell regeneration in metastasis (5K08CA230213-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982809. Licensed CC0.

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