Revolutionary Discovery: Antigen-Presenting Fibroblasts as Targets for Hard-to-Treat Cancers

Researchers at UT Southwestern Medical Center have uncovered a groundbreaking role of antigen-presenting cancer-associated fibroblasts (apCAFs) in tumor development and progression. Their study, published in Cancer Cell, reveals the existence of two distinct populations of apCAFs within tumors, which support cancer growth, metastasis, and resistance to treatment. These specialized fibroblasts are found in various cancers, including pancreatic cancer and colorectal cancer with peritoneal metastasis, and are primarily characterized by their ability to present immune molecules that influence immune cell activity.

The team employed advanced single-cell RNA sequencing of over 2.5 million cells across 15 cancer types, creating a comprehensive atlas that confirmed apCAFs are widespread in human cancers. Notably, they identified two subtypes: one linked to the mesothelium tissue lining body cavities and another originating from bone marrow. Spatial analysis demonstrated that mesothelium-associated apCAFs tend to cluster near cancer cells, while bone marrow-derived apCAFs are situated close to lymphocytes, suggesting they interact with different cellular components to promote tumor growth.

A key discovery was the production of secreted phosphoprotein 1 (SPP1) by both apCAF populations. SPP1 facilitates tumor proliferation and spread, as well as chemotherapy resistance. Genetic removal of SPP1 in mouse models slowed tumor growth and increased chemotherapy sensitivity, highlighting its potential as a therapeutic target and biomarker.

This research offers promising new avenues for cancer treatment, especially for patients with peritoneal metastasis of colorectal cancer, where treatment options are currently limited. Since drugs inhibiting SPP1 are already under clinical investigation for other conditions, there is potential for rapid translation into cancer therapies. These findings emphasize the importance of studying tumor microenvironments and developing targeted strategies to disrupt cancer-supportive stromal cells, ultimately improving outcomes for hard-to-treat cancers.