Breast Cancer Therapeutic Targets Revealed by Cellular Genomics

The tumor stroma consists of the basement membrane, fibroblasts, extracellular matrix, immune cells, and vasculature. It regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, which limits the development of stromal-targeted therapies. Now researchers from the Garvan Institute of Medical Research have discovered four new subtypes of cells within TNBC which may include new potential therapeutic targets.

The researchers discovered that one of the new cell types produces molecules that suppress immune cells, which may help cancer cells evade the body’s immune system. Their discovery may lead to new therapies for triple-negative breast cancer.

TNBC accounts for about 10–15% of all breast cancers. It differs from other types of invasive breast cancer in that it grows and spreads faster, has limited treatment options, and a worse prognosis. The term triple-negative breast cancer refers to the fact that the cancer cells lack three receptors: estrogen, progesterone, and the HER2 protein that are targeted with specialized therapies in other breast cancers.

The researchers searched for new potential targets for therapy by analyzing the individual cells inside negative breast tumors allowing them to identify subtypes of cells and investigate their role in disease.

Their study is published in the EMBO Journal in a paper titled, “Stromal cell diversity associated with immune evasion in human triple‐negative breast cancer,” and led by Alex Swarbrick, PhD, associate professor and head of the Tumor Progression Laboratory at Garvan Institute.

“In our study, we searched for new potential targets for therapy by analyzing the individual cells inside triple-negative breast tumors. This includes not only the cancer cells themselves, but also the surrounding host cells, such as immune and connective tissue cells, which can be thought of as the cancer ‘ecosystem’ that supports a tumor to grow and spread,” states Sunny Wu, a research assistant in senior author Alexander Swarbrick’s translational breast cancer research and tumor progression lab at the Garvan Institute of Medical Research and first author of the study.

The team used next-generation sequencing of 24,271 individual cells extracted from biopsy samples of five triple-negative breast cancer patients, and detected over 6,000 unique RNA molecules in every cell, creating a snapshot of each cell’s gene activity.

The researchers discovered four cell subtypes of stromal cells, by analyzing the profiles of active genes. Previous studies in triple-negative breast cancers had generally considered there to be only one type of stromal cell. Further investigation led to a surprising discovery of interactions between the signaling molecules produced by the stromal cells and immune cells.

“Our findings suggest that there is significant crosstalk between the immune system and stromal cells, which were generally thought to have only a structural role in cancers,” explained Swarbrick.

“Single‐cell RNA sequencing of five TNBCs revealed two cancer‐associated fibroblast (CAF) and two perivascular‐like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterized by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships, and functional properties in regulating the extracellular matrix. Using cell signaling predictions, we provide evidence that stromal‐immune crosstalk acts via a diverse array of immunoregulatory molecules,” noted the researchers.

The researchers also observed that one of the cell subtypes they discovered in the breast cancers, called inflammatory cancer-associated fibroblasts (iCAFs), released the chemokine CXCL12, a signaling molecule known to suppress the antitumor activity of T cells.

The team noted the significance in their findings since immunotherapy has limited response in many patients with TNBC. “If iCAFs are suppressing T cells in triple-negative breast cancer, and we can remove this interaction, T cells will be more susceptible to activation and more likely to attack the cancer,” added Swarbrick.

Combining immunotherapy with a treatment that stops the interaction between stromal cells and immune cells holds the potential for improving the treatment of TNBC.

Looking forward, the researchers will analyze breast cancer samples to have a better understanding of the cells that compromise triple-negative breast cancers, their interactions, and how they can be intervened with to stop disease progression.

“Pathologists have been describing cancers under the microscope for more than 150 years, but we still only have a shallow understanding of the cells that are there,” explained Swarbrick. “Cellular genomics is showing us that what we once thought of as one cell type is in reality a diversity of cell types, which will have a significant impact on how we tailor treatments in the future.”

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