# Structural and Functional Biology-based analysis of non-oncogene cancer dependencies

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $499,992

## Abstract

The Columbia Center for Cancer Systems Therapeutics (CaST) has successfully developed methodologies for
the patient-centric prioritization and evaluation of cancer therapeutic strategies. Through this cost extension we
seek to complete residual work related to the original CaST aims that was delayed due to the COVID-19
pandemic. Specifically, we will:
Assess the tumor replenishing potential of the oncogenic precursor cell population in pancreatic ductal
adenocarcinoma (PDA): In PDA we have inferred and experimentally validated the existence of three
transcriptionally distinct cell states. The most critical hypothesis emerging from these studies, as supported by
RNA velocity studies, is that the oncogenic precursor (OP) population – which unlike the other two, represents
a dominant component of all PDAs and was previously undetected – represents the key tumor maintenance
reservoir by replenishing both the morphogenic and the lineage sub-populations. To confirm this hypothesis,
which would be paradigm shifting in terms of our understanding of this tumor, we are planning barcode-based
lineage tracing assays in cell lines that we have already shown to comprise either OP and morphogenic cells
(KP4) or OP and lineage cells (CAPAN1).
Enhance the structure-informed annotation of the Cancer Homeostasis Proteins Database (CHoPD): One of the
key CaST deliverables, the CHoPD is a comprehensive, functionally and structurally annotated inventory of
master regulator (MR) proteins, compiled by systematically dissecting tumor checkpoints across samples from
publicly available repositories. The CHoPD has been implemented as a graph database in the Neo4j database
system and has been partially annotated with the standard cancer hallmarks as derived from PrePPI. We now
propose to incorporate the full repertoire of CaST structure-informed resources into this database, so as to create
a version of CHoPD that will contain extensive annotation derived from tools that have been developed in the
context of CaST Projects 1 and 3.
Complete development of a highly scalable platform for joint single-cell DNA and RNA sequencing: One of the
major technical objectives of CaST Project 2 is the development of scalable technology for simultaneous single
cell DNA- and RNA-seq. As previously reported, we have developed a novel asymmetric microwell array
technology for simultaneous co-encapsulation of thousands of individual cells with exactly two beads – one
harboring oligonucleotides for direct barcoding of genomic DNA and the other for mRNA capture and barcoding.
We have demonstrated that this device facilitates simultaneous solid-phase capture of mRNA and solution-phase
capture of gDNA from individual cells. Here we propose to complete the development of our DNA barcoding
beads and optimize the performance of our on-chip library construction for a full-scale demonstration of the
technology.
Infer copy number alterations from scRNA-Seq profiles in a collection of benchmark datasets:...

## Key facts

- **NIH application ID:** 10401148
- **Project number:** 3U54CA209997-05S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ANDREA CALIFANO
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $499,992
- **Award type:** 3
- **Project period:** 2021-08-12 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401148

## Citation

> US National Institutes of Health, RePORTER application 10401148, Structural and Functional Biology-based analysis of non-oncogene cancer dependencies (3U54CA209997-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401148. Licensed CC0.

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