# Tumor cell lineage diversity and composition in gastric cancer progression and therapy resistance

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $610,140

## Abstract

Gastric adenocarcinoma (GAC) remains one of the deadliest forms of cancer due to its rapid progression,
resistance to therapy, and a high rate of metastatic spread. A common site of metastases is the peritoneal
cavity that occurs in 40-50% of patients and leads to development of peritoneal carcinomatosis (PC). PC is
almost a universally lethal diagnosis with survival of less than 6 months due to limited therapeutic options that
are currently available. Intratumoral heterogeneity (ITH) is a fundamental property of GAC that contributes to
therapy resistance, disease progression and metastasis. We and others have characterized the genomic and
molecular ITH in GAC and PC, however, tumor cell lineage plasticity−the non-genetic, cell intrinsic origin of ITH
remains poorly understood. In our preliminary efforts to dissect the cellular and molecular ITH using single-cell
analysis, we discovered that the diversity in tumor cell lineage/state compositions appears to be an upstream
key regulator of phenotypic ITH of PC, beyond the genetic factors. We also find that tumors classified based on
tumor cell lineage/state compositions (cellular subtypes) are strongly associated with survival, exhibiting
differential activation of oncogenic pathways and distinct immune phenotypes. We therefore hypothesize that
tumor cell lineages/states dynamically evolve to resist treatment and promote tumor growth and its composition
determines phenotypes and outcomes of GACs. The goal of Aim 1 is to characterize tumor cell lineage/state
diversity and compositions in clinically defined GAC cohorts, determine their impacts on tumor cell clonal
evolution, and identity lineage features associated with GAC progression and metastasis. We will also profile
changes in tumor cell lineages and states in paired baseline and progressive tumors following chemotherapy
or immunotherapy, determine their impact on immune phenotypes and patient responses to anti-cancer
therapies, and identify lineage features associated with therapy resistance. In Aim 2, we will leverage our
genetically engineered mouse models (GEMMs) of GAC, follow the expansion and dissemination of cancer
cells in GEMMs over a period of time to longitudinally track and characterize dynamic changes in tumor cell
lineage identity and transcriptome states at single-cell resolution. We will investigate the clonal architecture of
tumor cells in different lineages/states and examine the dynamics of clonal populations that sustain tumor
growth at the primary sites, seed and colonize distant organs; we will also profile how tumor cells in different
lineages interact with TIME at the primary tumor site and influence invasion and dissemination. In Aim 3, we
will investigate tumor cell lineage plasticity in response to chemotherapy and immunotherapy in GEMMs. We
will characterize therapy-induced emergence of resistant cell lineages/states and identify the fundamental
pathways and drivers of lineage/state transition. This study will link ...

## Key facts

- **NIH application ID:** 10888167
- **Project number:** 5R01CA266280-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Pawel K. Mazur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $610,140
- **Award type:** 5
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888167

## Citation

> US National Institutes of Health, RePORTER application 10888167, Tumor cell lineage diversity and composition in gastric cancer progression and therapy resistance (5R01CA266280-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10888167. Licensed CC0.

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