# Project 2: 	: Systematic discovery of cell-extrinsic mechanisms of cancer drug resistance

> **NIH NIH U54** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $613,017

## Abstract

Project 2 – Project Summary
Tumors consist of millions of interacting cells, but our understanding of how those cells collectively respond to
therapeutic intervention is limited. This is because we have traditionally divided tumors from the “top-down” into
distinct cell types and then studied each population separately, focusing primarily on cancer cells. Yet, recent
studies have revealed that a cancer cell's behavior can be strongly affected by the molecules in its
microenvironment and its interactions with other cells (intercellular circuits). Unfortunately, our inability to
thoroughly measure and analyze each of these influences within the context of a tumor has limited our
capacity to fully grasp the mechanisms by which cancer cells evade therapeutic interventions in vivo.
To develop a deep and functional understanding of how these extrinsic tumor microenvironmental
factors influence the response of individual cancer cells to drugs, we need new approaches that are
capable of deeply and controllably profiling tumor cells and their interactions during treatment at
single-cell resolution. In particular, we need methods for: (1) identifying individual tumor-resident cells and
the molecules they secrete; (2) tracking the phenotypic responses (e.g., changes in size, shape, structure,
transcriptome) of cancer cells to controlled perturbations (drugs) in the presence of defined and physiologically
relevant factors (signaling molecules); and, (3) examining how cancer cell behaviors are directly impacted by
physical interactions with other cells in the tumor microenvironment. This degree of integration and control
would enable discovery of the regulators of in vivo cancer cell drug responses at unprecedented resolution.
Here, we aim to achieve these goals by combining three different, cutting-edge experimental platforms
– single-cell RNA-Seq (scRNA-Seq), suspended microchannel resonators (SMRs), and nanowells – to
systematically examine how the extracellular factors present in leukemias and colon and pancreatic
cancers influence drug responses. First, we will identify the signals and non-malignant cells present in each
tumor type by performing scRNA-Seq on primary biopsies from Core 1. With Core 2, we will generate an atlas
of implicated cell types/states and putative signaling molecules that may influence cancer cell drug responses
in vivo (Aim 1). Second, we will use SMRs and nanowells to systematically uncover how these soluble factors
and tumor cells inform on cancer cell drug responses (Aim 2); we will similarly examine the impact of
previously implicated environmental factors as well as other cancer cells (of the same and different intrinsic
states; from Project 1). By analyzing and modeling our results with Core 2, we will uncover previously
unknown microenvironmental synergies (e.g., cytokines, receptor-ligand pairing) that may modulate cancer cell
drug responses in vivo. Collectively, these aims will afford an unprecedented view of the tumor
m...

## Key facts

- **NIH application ID:** 10162309
- **Project number:** 5U54CA217377-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Alex K Shalek
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $613,017
- **Award type:** 5
- **Project period:** 2017-06-07 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162309

## Citation

> US National Institutes of Health, RePORTER application 10162309, Project 2: 	: Systematic discovery of cell-extrinsic mechanisms of cancer drug resistance (5U54CA217377-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10162309. Licensed CC0.

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