# Project 3: Neoplastic Cell Evolution

> **NIH NIH U54** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2020 · $274,273

## Abstract

Project 3 Abstract
 Cancer is an evolutionary process where a single cell grows into a visible tumor after it has acquired
multiple driver alterations and has created, or finds itself within, a permissive microenvironment. We will study
fundamental parameters of evolution (mutation, drift, selection, "MDS"), and microenvironmental features to
better understand their roles in colorectal cancer (CRC) outcomes. The innovation is that MDS-based
microenvironmental-aware biomarkers are direct measures of evolution. Such evolution-based biomarkers
reflect fundamental mechanisms for understanding what aspects of evolution most impact survival. To fully
characterize tumor evolution it is necessary to measure both how tumor cells evolve and the host ecology.
 In Aim 1, mutations detected by whole genome sequencing of 4 regions of 200 stage II and III CRCs
with long-term follow-up will be classified as public (clonal) and private (subclonal). CRCs will then be
subclassified with newly developed algorithms that can quantify selection (positive, neutral, negative) based on
subclonal mutation frequencies, where selection preferentially increases (positive) or decreases (negative)
subclonal mutation frequency. The same studies will be performed on small numbers of mouse and elephant
tumors to test whether neoplastic MDS parameters differ between species. In Aim 2, we will scan microscope
sections from the exact same regions sequenced in Aim 1, using a unique automated computational image
analysis platformthat can identify cells and quantify tumor microenvironments with respect to lymphocytes and
stromal cells. In particular, we will quantify potential immunoediting by the host, using lymphocyte colocalization
(Morisita index), lymphocyte density and Immunoscore, because prior studies indicate such host responses lead
to significantly better outcomes. To determine if host ecological heterogeneity reflects responses to specific
tumor subclones, we will overlay private mutation distributions on the same microscope slides. A correlation
between a specific subclone with a specific microenvironment is consistent with selection. No correlation
between specific ecological niches and tumor subclones is more consistent with neutral evolution, where all
subclones are equally well-adapted and subject to the same selection. We will combine tumor evolution and the
host reaction into a single evolution-ecology (Evo-Eco) index that summarizes the underlying evolutionary
struggle. For example, patients with aggressive tumors (positive selection) and supportive environments are
likely to have poorer outcomes relative to patients with tumorsunder negative selection and repressive
environments. We will validate any promising Evo-Eco index on a validation cohort of ~100 more CRCs in Aim
3. Data from this Project will be also analyzed in Project 1, and compared with the normal crypts in Project 2 to
determine if and how MDS parameters change in neoplasia. If successful, these studie...

## Key facts

- **NIH application ID:** 9900765
- **Project number:** 5U54CA217376-03
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Darryl K Shibata
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $274,273
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900765

## Citation

> US National Institutes of Health, RePORTER application 9900765, Project 3: Neoplastic Cell Evolution (5U54CA217376-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9900765. Licensed CC0.

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