Many cancers that initially respond to therapy later relapse as metastatic disease, with the cancer widely spread throughout a patient’s body. The cells that seed these dispersed sites can remain in a quiescent state for months or even years before roaring back to life and producing cancer even more intransigent to treatment. Distant metastases underlie more than 90 percent of deaths from cancer.
Understanding the molecular underpinnings of how these latent cancer cells evade the immune system, as well as cancer therapy, has the potential to transform cancer medicine.
Cancer biologist Srinivas Malladi was recruited in 2017 from Memorial Sloan-Kettering Cancer Center, where he was a research associate, to the University of Texas Southwestern Medical Center department of pathology. Malladi returns to Texas, where he studied as a graduate student, with the help of a First-Time Tenure-Track Award from CPRIT.
Even in early-diagnosed patients, cancers may have already spread the seeds of metastasis around a patient’s body before the patient is diagnosed. These metastatic seeds can enter a state of dormancy and may be undetectable until years or decades later, when they give rise to metastasis.
Malladi is trying to figure out what keeps these cells in a state of dormancy and coaxes them back to life; as well as either how to detect and destroy them or prevent them from proliferating. He is studying this latent metastasis, which is clinically observed in lung, breast, and kidney cancer patients, using mice as a model system.
“We are trying to figure out how cancer cells within the primary tumor become invasive and survive at secondary or metastatic sites in the body. Different cancers have a tendency to metastasize to the same organs: lung, brain, bone,” Malladi says. “We think it has to do with certain organs being more receptive, by providing access and essential factors that aid cancer cell survival.”
Most researchers studying metastatic disease look for tumors actively growing at sites distant from the site of origin. But Malladi is specifically looking for metastatic seeds that survive in these metastatic sites but don’t actually grow. He’s found that these cells enter into a quiescent, cloaked state, which enables them to survive and evade detection by the immune system.
These cells also avoid being killed by chemotherapy, because most current treatments mostly kill rapidly dividing cells, which these are not. “We think they behave more like stem cell populations,” he says, “which are not rapidly dividing, but given the right stimulus or conducive environment, can divide rapidly and replenish tissue — or in the case of cancer, initiate metastasis.”
He hasn’t found yet what causes the latent cancer cells to leave this state of quiet co-existence and grow into fatal tumors. He’s exploring possible theories, such as that the cells eventually modify the host organ to provide them with growth factors, or find a way to begin growing unchecked, evading immune surveillance.
He’s hoping to find biomarkers or other signs in cancer cells that would help clinicians know which patients need to be more closely monitored for signs of metastasis even after their disease appears to be cured.
Malladi received his undergraduate education at Acharya N.G. Ranga Agricultural University in Hyderabad, India, and came to the U.S. for master’s degrees in business management and biology & biochemistry, which he received at Texas A&M University. He received his Ph.D. in cancer biology from the University of Texas, and then began a postdoctoral fellowship at Memorial Sloan-Kettering in 2010.
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