# Deconstructing the collective invasion pack to define Myo10 function

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $339,008

## Abstract

Project Summary
Collective invasion is a major mode of metastasis observed in patients across most solid tumor types. How the
collective invasion pack operates, communicates, and navigates as a single cohesive unit remains unclear. To
address this, we published on an image-guided genomics platform to isolate any living cell(s) within a collective
invasion pack, and expand the population for genomic and molecular analysis, a technique termed
Spatiotemporal Cellular & Genomic Analysis (SaGA). We used SaGA to dissect the molecular, epigenetic, and
genomic profiles of leader and follower cells invading as a hierarchical cohesive unit. To determine how
epigenetic reprogramming drives this phenotypic heterogeneity, we deconstructed the collective invasion pack
using SaGA, then integrated genome-wide promoter methylation and transcriptome data to define differentially
methylated regions within the leader and follower phenotypes. We observe global epigenomic re-wiring in leader
cells supporting an epigenetic basis for the phenotypic heterogeneity within the collective invasion pack. We then
identified Myo10 (myosinX) as a top differentially methylated and expressed gene, where the leader cell
promoter is hypomethylated, and leaders in several lung cancer lines overexpress Myo10. Myo10 is a canonical
modulator of filopodia elongation and we show it drives filopodia elongation, collective invasion, leader cell-driven
fibronectin micropatterning (fibrillogenesis), and is transcriptionally activated by Jag1/Notch. We will use this
information to test a mechanistic model with the overarching hypothesis that Myo10 activation via promoter
hypomethylation in leader cells drives filopodia-based micropatterning of fibronectin to create a leader cell-driven
collective invasion path. We propose that this leads to an invasive advantage for lung cancer cells resulting in
metastatic disease. In Aim 1 we test the model that Myo10 hypomethylation in leaders allows for Jag1/Notch1-
driven transcriptional activation, driving filopodia elongation, and fibronectin micropatterning. In Aim 2 we test
how this collective invasion pathway impacts metastasis using in vivo metastasis models and the first patient-
derived leader cells. Throughout, we leverage unique resources developed here including SaGA-derived cell
lines, ex vivo imaging, and patient-derived lung cancer leader cells. We speculate that these data will provide
mechanistic insight into collective invasion and translational value towards understanding lung cancer patient
leader cell biology.

## Key facts

- **NIH application ID:** 10830982
- **Project number:** 5R01CA250422-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Adam I. Marcus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,008
- **Award type:** 5
- **Project period:** 2020-05-06 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830982

## Citation

> US National Institutes of Health, RePORTER application 10830982, Deconstructing the collective invasion pack to define Myo10 function (5R01CA250422-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10830982. Licensed CC0.

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