# Project-2:Defining the role of compartmentalized neuro-lymphatic networks on CRC and metastatic progression

> **NIH NIH U54** · ROCKEFELLER UNIVERSITY · 2024 · $307,398

## Abstract

Colorectal cancer (CRC) is the second most deadly cancer in the United States, affecting over 140,000 people
each year, killing approximately 50,000 in the US, largely by metastatic progression. The intestine hosts the
body’s largest collection of immune cells, maintained in close proximity to foreign antigens from the diet, enriched
in the proximal regions, and microbiota, which accumulate in the distal regions. The vast and highly connected
gut lymphatic vessels form a major cell- and antigen transport route to the draining lymph nodes, responsible for
the initiation of adaptive immunity, which could play four roles in regulating colorectal cancer metastasis: immune
cells could (i) prevent CRC progression and early dissemination or metastasis by immune-cell killing (ii) promote
CRC progression and metastasis through release of inflammatory cytokines, (iii) prevent metastatic colonization
in the liver, or (iv) promote metastatic colonization in the liver. We provide data that compartmentalization of
intestinal lymphatic drainage to functionally distinct lymph nodes facilitates the simultaneous induction of
immune-suppressive and inflammatory immune responses in the gut; however, the relevance of gut lymphatics
to CRC and metastasis remains underexplored. In addition to compartmentalized lymphatic networks, the gut
also hosts a large number of enteric neurons functionally tuned to each region they occupy. Using retrograde
tracing from distinct intestinal regions and specific cell-sorting independent transcriptomics, we uncovered novel
neuronal circuits and a role for enteric neurons in sensing perturbations in the intestinal tissue; whether enteric
neurons sense and modulate CRC metastatic progression remains unknown. Overall, Project 2 is focused on
understanding how enteric-associated neurons sense and provide signals that regulate CRC progression and
liver dissemination and how compartmentalized intestinal lymphatic drainage of primary tumor and metastatic
liver sites regulate anti-tumor responses and early dissemination. In Aim 1, we hypothesize that primary CRC,
as well as liver metastasis, are specifically sensed by populations of enteric-associated neurons, which in turn,
influence tumor and metastatic progression. This question will be addressed using tools to visualize and circuit-
map, single cell and active translating transcriptomics, and chemogenetic approaches targeting specific neuronal
subsets. In Aim 2, we hypothesize that the intestinal lymphatic system communicates primary CRC and early
metastatic seeding to the local and systemic immune system, modulating anti-tumor responses. This will be
addressed combining modern clearing and live imaging techniques, single cell transcriptomics and novel immune
cell-interaction approaches. By combining these approaches, expertise of Mucida lab, with Sohail Tavazoie lab’s
expertise in cancer and metastasis biology (Project 1), the Birsoy lab’s expertise in in vitro screenings and cell
metabo...

## Key facts

- **NIH application ID:** 10909179
- **Project number:** 5U54CA261701-04
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Daniel S Mucida
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $307,398
- **Award type:** 5
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909179

## Citation

> US National Institutes of Health, RePORTER application 10909179, Project-2:Defining the role of compartmentalized neuro-lymphatic networks on CRC and metastatic progression (5U54CA261701-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909179. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*