#malignancies

A stained histological slide, magnified 100 times, depicts cancer cells expansively spread through normal breast tissues, including a duct completely filled with tumor cells. Credit: Dr. Cecil Fox, National Cancer Institute

Researchers describe how malignancies leverage evolution and basic cellular functions to promote immune dysfunction and a better future for themselves

Writing in EMBO reports, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumor survival and growth.

Cancer is driven by multiple types of genetic alterations, including DNA mutations and copy number alterations ranging in scale from small insertions and deletions to whole genome duplication events.

Collectively, somatic copy number alterations in tumors frequently result in an abnormal number of chromosomes, termed aneuploidy, which has been shown to promote tumor development by increasing genetic diversity, instability and evolution. Approximately 90 percent of solid tumors and half of blood cancers present some form of aneuploidy, which is associated with tumor progression and poor prognoses.

In recent years, it has become apparent that cells cohabiting within a tumor microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients), but also to the internal stressor aneuploidy. Both activate a stress response mechanism called the unfolded protein response (UPR), which leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) of cells — an organelle that synthesizes proteins and transports them outside the cell.  

When this primary transport/export system is disrupted, UPR attempts to restore normal function by halting the accumulation of misfolded proteins, degrading and removing them and activating signaling pathways to promote proper protein folding.

If homeostasis or equilibrium is not re-established quickly, non-tumor cells undergo cell death. Conversely, cancer cells thrive in this chaos, establishing a higher tolerance threshold that favors their survival.

“In these circumstances, they also co-opt neighboring cells in a spiral of deceit that progressively impairs local immune cells,” said co-senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and a tumor immunologist at Moores Cancer Center with Hannah Carter, PhD, associate professor of medicine and a computational biologist. Zanetti had previously introduced the hypothesis in a Sciencecommentary.

The researchers hypothesized that aneuploidy, UPR and immune cell dysregulation could be linked together in a deadly triangle. In the new study, Zanetti, Carter and colleagues analyzed 9,375 human tumor samples and found that cancer cell aneuploidy intersects preferentially with certain branches of the signaling response to stress and that this finding correlates with the damaging effects of aneuploidy on T lymphocytes, a type of immune cell.

“This was an ambitious goal not attempted before,” said Zanetti. “It was like interrogating three chief systems together — chromosomal abnormalities in toto, signaling mechanisms in response to endogenous stress and dysregulation of neighboring immune cells — just to prove a bold hypothesis.

“We knew the task would be challenging,” added Carter, “and that we would need to create and refine new analytical tools to test our hypotheses in heterogeneous human tumor data, but it was a worthwhile risk to take.”  

The findings, they said, show that the stress response in cancer cells serves as an unpredicted link between aneuploidy and immune cells to “diminish immune competence and anti-tumor effects.” It also demonstrates that molecules released by aneuploid cells affect another type of immune cells — macrophages — by subverting their normal function to turn them into tumor-promoting actors.

“Tumor Reasons Why Cancers Thrive in Chromosomal Chaos”

Molecular profiling is more often used after standard cancer treatments have failed, but a new study suggests that it could effectively guide first-line treatment, especially for poor-prognosis cancers

In treating cancer, personalized medicine means recognizing that the same disease can behave differently from one patient to another, and precision medicine means that diagnosis and treatment should involve understanding the specific genetic makeup of each patient’s tumor and disease.

In a recent study, published October 4, 2021 in Genome Medicine, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health, with colleagues elsewhere, report that conducting genomic evaluations of advanced malignancies can be effective in guiding first-line-of-treatment, rather than waiting until standard-of-care therapies have failed.

By their nature, cancers are molecularly complex, each with a heterogeneous combination of genetic mutations that, more often than not, defy easy treatment. With every stage and line of therapy, tumor cells adapt to become more resistant to remedy.

The study authors hypothesized that developing matched, individualized combination therapies for patients with advanced cancers who had not been previously treated might be feasible and effective.

Just under 150 adults with newly diagnosed cases of advance malignancies were enrolled in the prospective study at two sites: Moores Cancer Center and Avera Cancer Institute in Sioux Falls, South Dakota. The patients had either incurable, lethal cancers (at least a 50 percent cancer-associated mortality rate within two years) or they had a rare tumor with no approved therapies.

Researchers performed extensive genomic profiling of all patients, identifying and documenting all detectable gene mutations to create a molecular profile of each patient’s tumor that would guide their precision cancer therapy.

“Each patient received a personalized N-of-1 treatment plan that optimally matched therapeutic agents to their tumor’s distinct biology, while also taking into account other variables, such as underlying conditions or co-morbidities unique to that patient,” said first author Jason Sicklick, MD, professor of surgery at UC San Diego School of Medicine and surgical oncologist at Moores Cancer Center.

Pictured: Cancer cells ( Thomas Deerinck)

“At Initial Cancer Diagnosis, a Deeply Personalized Assessment”