# Single-Cell, Spatial and Functional Dissection of Cancer Cell States, Co-Evolving Ecosystems, and Vulnerabilities During Tumor Progression and Metastasis

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $349,808

## Abstract

Aggressive cancers often lack pharmacologically actionable mutations and do not respond to immune checkpoint 
blockade, thus deriving only modest clinical benefit from targeted and immune therapy. The heterogeneity of 
both transformed and healthy cells in the Tumor Microenvironment (TME) represents a critical obstacle to 
achieving more durable response in cancer patients. Recent insights, using multi-omics approaches, have shown 
that cancer cells can exist in a variety of transcriptionally distinct, yet co-existing states, some of which are 
already primed for metastatic progression or drug resistance. The plasticity of these states—i.e., the ability of 
cancer cells to reprogram across multiple states, either spontaneously or because of drug perturbations—and 
their homeostatic coexistence with other TME subpopulation, via paracrine molecular interactions, creates a 
constant challenge to therapeutic approaches by fostering the emergence of drug-resistance, tumor progression, 
and the creation of a pro-malignant, immunosuppressive milieu. Malignant states and transitions are only partially 
explained by sequential acquisition of somatic mutations, suggesting that they result from integration of a variety 
of cell-intrinsic and -extrinsic molecular cues that determine their lineage attribution, establishment, and 
interconversion. To date, several technical, clinical, and analytical challenges have hampered a comprehensive 
understanding of the natural biology of these processes in patients. Project 2 is dedicated to resolving the 
variability and plasticity of malignant cells and of the healthy cells that define the TME by developing and applying
a battery of technical and analytical tools for the dissection of cancer heterogeneity at the single-cell level, and 
for the nomination, validation and testing of novel drivers of tumor-progression and therapy response and 
resistance. We will delineate these concepts in a defined biological context, that is the progression from a primary 
tumor towards brain-metastatic disease. To this end, we will leverage a series of innovations from CaST 
investigators, including (a) multi-modal single-cell profiling from archival tissues, (b) simultaneous low-pass
whole-genome sequencing (lpWGS) of the same cell pool, (c) integrated single-cell and spatial single-cell 
transcriptomics, (d) analytical approaches to integrate and model multi-modal single-cell data in space, time and 
context of interactions among cells, (e) tools to elucidate cell state stability and transitions, (f) combinations of 
genome-editing perturbations with single-cell read outs that can be linked to drug screens via gene expression 
profiling, and (g) network-based Master Regulator analyses to elucidate mechanistic determinants of 
transcriptional cell state. This will be extended by experimental innovations, that (h) accurately model tumor 
progression in vivo and recapitulate entire human ecosystems, (i) enable labeling of metastatic...

## Key facts

- **NIH application ID:** 11171865
- **Project number:** 5U54CA274506-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Benjamin Izar
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $349,808
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11171865

## Citation

> US National Institutes of Health, RePORTER application 11171865, Single-Cell, Spatial and Functional Dissection of Cancer Cell States, Co-Evolving Ecosystems, and Vulnerabilities During Tumor Progression and Metastasis (5U54CA274506-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11171865. Licensed CC0.

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