SWCRF grantees at Mount Sinai identify how primary tumor cells are programmed for dormancy and evade chemo after spread


The Samuel Waxman Cancer Research Foundation congratulates grantee Julio A. Aguirre-Ghiso, PhD, of the Icahn School of Medicine at Mount Sinai, whose tumor dormancy team published research in Nature Cell Biology that identifies conditions by which specific signals in primary tumors of head and neck and breast cancers pre-program cancer cells to become dormant and evade chemotherapy after spreading. Their findings could lead to new drug development and treatment options and transform the way doctors care for cancer patients to treat metastatic disease.

Hypoxia, a condition of having low oxygen in tissues, is a microenvironmental hallmark of solid tumors that induces stress responses, dormancy and resistance to chemotherapy and radiation. Until now it has been unclear how hypoxia in primary tumors influences the fate of disseminated tumor cells (DTCs) in target organs and how this is related to patient outcome. This study states that primary tumor hypoxic microenvironments give rise to dormant tumor cells that evade therapy and may be the source of cancer relapse and poor prognosis.

"This research highlights the signals in the primary tumor that instruct disseminated cancer cells to become dormant," said Dr. Aguirre-Ghiso, Professor of Medicine, Hematology and Medical Oncology, The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai. "Dormant cells must be targeted to address the whole spectrum of the disease and attacking the cancer. We hope this research may lead to the use of dormancy markers in primary tumors to assess the prevalence of disseminated cancer cells in secondary organs and thus tailor treatments to eliminate these dormant and therapy-evading cancer cells."

Aguirre-Ghiso and a team of investigators from Albert Einstein College of Medicine, SUNY Polytechnic Institute and University of Wisconsin-Madison developed a device using a nano-technology tool, biosensors, and advanced imaging technology to manipulate primary tumor microenvironments. They created controlled hypoxic and non-hypoxic niches in tumors by implanting the devices loaded with drugs that induced hypoxia. These "fine-tuned" microenvironments in live tumors allowed the researchers to isolate the cancer cells to determine how they behaved when they moved from the primary tumor to the lungs. The investigators tracked the tumor cells with genetically encoded biosensors to see which cells were exposed to low oxygen, which cells were dormant, and how they reacted to therapy.

The investigators discovered DTCs from hypoxic regions were still able to grow into metastasis and more likely to enter dormancy as opposed to cells from high oxygen levels in primary tumors. The researchers thus found that hypoxic regions of the tumor could spread not only rapidly, growing DTC's but also sending a large amount of them into a "sleeping mode" whereby creating cells more efficient at evading chemotherapy.

The findings suggest that a marker test might be able to predict which patients might be prone to carry more dormant drug-resistant cancer cells.


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