# Functional and molecular characterization of Oncofetal Stem Cells in CRC

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $560,297

## Abstract

Functional and molecular characterization of Oncofetal Stem Cells in CRC
Project Summary.
Background. Colorectal cancer (CRC) is the second most deadly cancer worldwide, with nearly one million
deaths annually1. CRC develops as a result of accumulating genetic and epigenetic aberrations in the colonic
epithelium leading to formation of benign adenomas that evolve to invasive adenocarcinomas 2,3. Despite the
advances in treatment options, resistance to therapy and recurrence remain inevitable in patients with advanced
disease, accounting for the high mortality rates 4,5. The underlying malignant features have been often attributed
to the LGR5+ CSCs. However, the unexpected findings that certain LGR5- cells sustain tumor growth upon
selective ablation of this population 6,7 are consistent with the recent description of a potential second stem cell
population, with fetal-like characteristics 8-10. While this is intriguing from a therapeutic perspective, existence of
a second, plastic, stem cell population in a more primitive state (hereafter referred to as OnFSCs for OncoFetal
Stem Cells) is solely based on transcriptional signatures.
Gap. Despite recent studies describing its existence, the molecular underpinnings, functional relevance, and
therapeutic implications of the OnF cellular state in CRC remain largely unexplored.
 Hypothesis. We hypothesize that OnFSCs work in tandem with the LGR5+ stem cells (SCs) to fuel tumor
evolution in CRC. OnF cells emerge early during intestinal tumorigenesis (i.e. upon inactivation of the APC
gatekeeper). Their resistance to therapy and high regenerative potential makes them a critical driver of tumor
plasticity and cancer recurrence.
 Specific Aims. We here propose to functionally characterize the OnFSCs in CRC.
In Aim1, we will first generate phenotypic transcriptional reporters to track the dynamics of the LGR5+ CSCs and
OnFSCs. Then, by coupling these reporters to a suicide gene (i.e. DTR), we aim to dissect the functional interplay
between these different stem cell pools in CRC.
In Aim2, we will use a multi-omic approach to determine the molecular drivers of the OnF state and phenotypic
plasticity in CRC.
In Aim3 we will perform targeted phenotypic screening to identify compounds able to selectively deplete
OnFSCs. The top hits will be tested in combination with the current standard of care or LGR5+SC-targeting
therapies11,12. We will validate our top drug combinations in vivo using both mouse tumoroids and human PDOs
and/or PDXs. The aim is to determine a selective combination therapy superior to the current standard of care.
 Impact. The findings of these studies will uncover a new layer of complexity in CRC biology and will establish
a mechanistic foundation for designing effective combination therapies with enduring impact on CRC treatment.

## Key facts

- **NIH application ID:** 10942200
- **Project number:** 1R01CA292376-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Slim Mzoughi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $560,297
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942200

## Citation

> US National Institutes of Health, RePORTER application 10942200, Functional and molecular characterization of Oncofetal Stem Cells in CRC (1R01CA292376-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10942200. Licensed CC0.

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