DCIS Cell Atlas Reveals Clues to Invasive Breast Cancer Progression

Researchers at The University of Texas MD Anderson Cancer Center have created what they say is one of the most detailed maps to date of the tumor microenvironment (TME) surrounding estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS), the most common form of preinvasive—stage 0—breast cancer. The atlas was created by analyzing samples from normal breast tissue, DCIS and invasive breast cancers.

The study findings may help to explain why some lesions progress to invasive breast cancer and others do not and inform strategies for improving patient risk prediction and developing better targeted approaches for those at higher risk of invasive disease.

“DCIS is considered a snapshot before breast cancer becomes invasive, but not all DCIS cases progress to invasive disease, and the biology surrounding these lesions has been challenging to examine,” said research co-lead Nicholas Navin, PhD, chair of Systems Biology. “This atlas reveals the surrounding cells and structures that may help disease become invasive. In the future, these findings may allow clinicians to better identify and treat patients with DCIS who are at higher risk of invasive progression while also avoiding unnecessary treatments for those at low risk.”

Navin, together with research co-lead Savitri Krishnamurthy, MD, professor of Anatomical Pathology, as well as co-first authors Siyuan He, PhD, and Aatish Thennavan, PhD, postdoctoral fellows of Systems Biology, and colleagues, reported on their findings in Science, in a paper titled “A cellular atlas of the preinvasive breast cancer microenvironment.” In their report the team stated that their data “… greatly improve our fundamental understanding of the DCIS microenvironment and the progression of invasive disease.”

DCIS occurs when abnormal cells grow inside the breast milk ducts but have not yet spread into surrounding tissue, and is considered to be a precursor to the most common type of breast cancer. “Ductal carcinoma in situ (DCIS) is precursor of invasive ductal carcinoma (IDC), in which the preinvasive cells are confined within the basement membrane of breast ductal-lobular structures,” the authors wrote.

Mammograms and other breast examinations have increased the detection of DCIS cases, but many of these lesions never progress to invasive disease, making it challenging to determine which patients actually need more aggressive treatment. “Over the last three decades, routine breast mammography screening has led to overdiagnosis of DCIS that now represents up to 25% of all diagnosed breast cancer cases,” the team continued. “If left untreated, only 10-30% of women with DCIS will progress to invasive disease.”

While genetic changes in DCIS have been well-studied, little is known about its tumor microenvironment—the community of immune cells, blood vessels and tissue cells that surround and interact with the cancer cells. The researchers set out to generate a comprehensive cell atlas for DCIS. Using advanced single-cell and spatial profiling technologies, they mapped more than 850,000 cells from samples of normal breast tissue, DCIS and invasive breast cancer. They identified extensive changes in cancer cells and the surrounding microenvironment as disease progressed. “We analyzed 854,911 cells from 159 patients by single cell RNA sequencing and 39 samples by spatial transcriptomics, which identified nine cell types and 60 cell states,” they reported.

The resulting detailed atlas suggests that important biological features associated with invasive breast cancer begin to emerge earlier than previously known. The study also uncovered previously unknown “cancer stromal loops,” ring-like structures made of supportive tissue and vascular cells that surround DCIS lesions, which create conditions that support tumor growth. “Our data reports on remodeling of specific immune, stromal cell types and myoepithelial cells in the DCIS TME, along with changes in cancer cell metaprograms that form cellular ecosystems and spatial niches to support the growth and progression of DCIS,” they wrote in summary.

Additional research is needed to validate these findings and evaluate their potential use in future diagnostic tools and prevention or treatment strategies. The findings could one day help doctors predict which patients need aggressive treatment and which patients may safely avoid it.  The team said researchers will continue studying the cellular features identified in the atlas to determine whether they can predict which DCIS lesions are most likely to become invasive, to help better determine the best strategies for individual patients.

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